Walsh and Hoyt's Clinical Neuro-Ophthalmology

Viruses (Except Retroviruses) and Viral Diseases - Part 2

"Viruses are important causes not only of human systemic disease but also of neurologic and visual disease. It is not the purpose of this chapter to consider all known viruses that produce human disease or to consider all diseases produced by those viruses. Instead, we will restrict this chapter to those viruses that produce disease of neuro-ophthalmologic significance, with the exception of retroviruses, which are of such unique importance that they are discussed in Chapter 58."

3228 CLINICAL NEURO-OPHTHALMOLOGY seems to be antigenically more similar to the Japanese en-cephalitis virus (1676). Too few cases of Negishi encephali-tis are described (1677) to provide an accurate description of either its neurologic manifestations or its prognosis. Powassan Virus Powassan virus was isolated from a child with encephalitis in Canada in 1958 (1678), and the virus was named after the Ontario town where the patient resided. It is a member of the tick-borne encephalitis group of viruses and is antigen-ically very similar to the virus that produces Russian spring-summer encephalitis (1379). The virus can be isolated from a variety of Ixodes and Dermacentor ticks, especially I. marxi, I. cookei, and D. andersoni (1386,1634); I. spinipal-pus is a specific vector for Powassan virus in the western United States (1679). The life cycle of these ticks involves such wild animals as squirrels, porcupines, and groundhogs. Humans are accidental hosts that usually are infected by the bites of ticks in their natural habitat or in the home after the ticks are brought inside by domestic animals. Goats and cows can also become infected by the bite of infected ticks, however, and such animals may produce infected milk that can be a source of infection, as occurs in Central European encephalitis. Human infection by Powassan virus is rare (1386). sero-logic surveys in enzootic areas indicate seropositivity in 0.5-4% of persons (1379). Of those infected, a very small number develop neurologic disease: Powassan encephalitis (1631,1680-1683). From 1958 to 1998, 27 Powassan en-cephalitis cases were reported from Canada and the north-eastern United Sates, and in 1999 to 2001, four cases were reported from Maine and Vermont residents (1683). The clinical features of Powassan encephalitis usually are identical with those of Russian spring-summer encephalitis. It is a monophasic illness that begins about 7-10 days after inoculation of the virus by a tick bite (1387). About 25% of symptomatic patients develop sudden fever, headache, photophobia, nausea, vomiting, and nuchal rigidity consis-tent with an aseptic meningitis (1684). The remaining 75% of patients develop more severe neurologic manifestations consistent with a meningoencephalitis, including alterations in mentation, progressive somnolence, focal weakness, pa-ralysis, and seizures (1681,1682). Focal deficits occur in more than 50% of cases. In one patient, olfactory hallucina-tions, focal seizures, and a temporal lobe focus of EEG dis-turbances suggested a diagnosis of HSV encephalitis until appropriate serologic studies to detect antibodies to Powas-san virus were performed (1685). Some patients with Powas-san encephalitis develop symptoms and signs of vestibu-locerebellar dysfunction, including dizziness, vertigo, oscillopsia, difficulties with balance, ataxia, and dysmetria (1684). Such patients may have a variety of disturbances of fixation and ocular motility, including vestibular nystagmus, ocular dysmetria, saccadic pursuit, square-wave jerks, and ophthalmoplegia (1686). In patients with this form of the disease, the differentiation from Russian spring-summer en-cephalitis is clear. Treatment of Powassan encephalitis is supportive. Most patients survive, although fatalities occur, and some survi-vors have persistent neurologic sequelae, such as hemipare-sis, quadriparesis, and aphasia (1386,1679). Prevention of Powassan encephalitis includes avoidance of tick-infested areas, appropriate dress, and the use of acaricides and repel-lents. Drinking unpasteurized milk should be avoided. Hepatitis C Virus (HCV) The hepatitis C virus is a single-stranded RNA virus that belongs to the family Flaviviridae (1687). Although this virus rarely causes major neurologic or visual disease, infec-tion with HCV is the most common cause of chronic viral hepatitis, in the Western world and ranks only slightly below chronic alcoholism as a cause of cirrhosis, end-stage liver disease, and hepatocellular carcinoma in the United States (1687). Hepatitis C is generally transmitted during sexual contact or blood transfusion (1687). Although it does not usually produce visual deficits, HCV infection has been associated with keratitis (1688). Chronic HCV infection may be associated with decreased tear vol-ume and decreased tear lactoferrin concentration, suggesting that there may be dysfunction of the lacrimal glands in pa-tients with this infection (1689). Quillen et al. (1690) de-scribed a case of acute retinal pigment epitheliitis that oc-curred in the macula of the right eye in a 22-year-old woman with serologically proven HCV infection. Neurologic complications of HCV infection also are un-common, but reported associations include anterior optic neuropathy, acute encephalitis or encephalomyelitis, acute disseminated encephalomyelitis, myelopathy, cryoglobuli-nemic and vasculitic neuropathy, distal axonal polyneuropa-thy, mononeuritis multiplex, Guillain-Barre´ syndrome, chronic inflammatory demyelinating polyradiculoneuropa-thy (CIDP), restless legs syndrome, and myasthenia gravis (1690-1701). Tembl et al. (1696) described nine patients with neurologic complications of HCV infection. Seven pa-tients presented with a combination of a chronic sensory polyneuropathy, mononeuritis multiplex, and encephalopa-thy related to hepatitis C-related cryoglobulinemia. The non-cryoglobulinemic associations included anterior optic neu-ropathy and restless legs syndrome with small-fiber neuropa-thy. Corticosteroids and cyclophosphamide may be useful in controlling neurologic difficulties related to vasculitis (1696). HCV RNA may be detected in tears and aqueous humor by PCR in patients with anti-HCV antibody in their blood, suggesting that corneas from HCV antibody-positive donors may be contaminated by the virus (1702). Therapy for pa-tients with chronic hepatitis C includes interferon-alpha, often combined with ribavirin (128,1686). Asymptomatic retinopathy occurred in 8 of 19 patients treated with inter-feron- alpha and ribavirin for chronic HCV infection (1703). Retinal changes were transient and disappeared while the patients were still being treated. ORTHOMYXOVIRIDAE The viruses in the family Orthomyxoviridae were once grouped together with several other viruses, including the VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3229 mumps and measles viruses, in a single family, Myxoviridae (1630). The name ‘‘myxovirus'' was chosen to denote the unique affinity of some of these viruses for glycoproteins (from the Greek myxa, meaning ‘‘mucous''). The myxovi-ruses subsequently were separated into two families, the Or-thomyxoviridae and the Paramyxoviridae, on the basis of morphologic and genetic differences. Characteristics The orthomyxoviruses are enveloped helical nucleocap-sids covered with surface projections or spikes consisting of glycoproteins that possess either hemagglutinin or neuram-inidase activity (1630). These spikes allow the virus to attach to host cells to initiate infection. They are also one of the major antigens of the virus. Influenza Viruses The viruses that make up the family Orthomyxoviridae belong to a single genus: Influenza virus. The viral species within this genus are subdivided into four main groups based on differences in antigenicity of their nucleoprotein: (a) in-fluenza virus type A; (b) influenza virus type B; (c) influenza virus type C; and (d) swine influenza virus (1630). Epidemiology One of the unique and most remarkable features of influ-enza viruses is the frequency with which changes in antige-nicity occur. Such antigenic variation occurs almost annually with influenza A virus but is less frequent with influenza B and does not occur with influenza C (1704). It is this anti-genic variation that leads to repeated human infection with variants of influenza A virus, to which there is little or no resistance, and helps explain why influenza continues to be a major epidemic human disease. Although the nucleoprotein of the influenza viruses is re-sponsible for the antigenic variations between types A and B, antigenic variation principally involves the two external glycoproteins of the virus. The hemagglutinin glycoprotein is the more important antigen because it is more frequently involved in antigenic variation than is the neuraminidase glycoprotein, and also because antibody to hemagglutinin glycoprotein neutralizes infection. Antigenic variation is called antigenic drift or antigenic shift, depending on whether the variation is small or large, respectively. It is antigenic shift that produces ‘‘new'' viruses to which hu-mans have little or no resistance. Influenza virus infection is acquired through inhalation of virus-containing respiratory secretions (1704). Person-to-person transmission readily occurs in part because large numbers of influenza viruses are present in respiratory secre-tions of infected persons at the time of illness. Once influ-enza virus is inhaled, it is deposited on the epithelium of the respiratory tract. It may then attach to and penetrate the columnar epithelial cells. Once adsorption occurs, the virus initiates a replication cycle that requires 4-6 hours for com-pletion (1704). Release of virus then continues for several hours before cell death occurs. Released virus may then initi-ate infection in adjacent and nearby cells, so that within a few replication cycles, a large number of cells in the respira-tory tract are releasing virus and dying from replication of influenza virus. The duration of the incubation period to the onset of clinical symptoms varies from 18 to 72 hours, depending in part on the dose of the inoculum (1704). Clinical Manifestations of Influenza Virus Infection (Influenza) Clinical infection with influenza type A or B virus most often produces influenza, a febrile illness that usually occurs in outbreaks of varying severity almost every fall and winter and that usually is self-limited. The attack rates during such outbreaks may be as high as 10-40% over a 5- to 6-week period (1704). In contrast, infection with influenza C virus causes afebrile common colds and rarely, if ever, produces an influenza syndrome. The most common clinical manifestations of influenza are fever, myalgias, and cough; however, some patients develop pharyngitis, croup, tracheobronchitis, bronchiolitis, or pneu-monia. Cough is the most frequent and troublesome of the respiratory manifestations of influenza. It may be accompa-nied by substernal discomfort or burning. Nasal obstruction and clear nasal discharge occur, but not to the degree seen in common colds caused by rhinovirus. The mucous mem-branes of the nose and throat are hyperemic, but there is no exudate, and small tender cervical lymph nodes may be present. Pharyngeal pain is common. Most of these manifes-tations persist for about 3-4 days after the fever subsides, and the patient then enters a convalescent period that lasts several weeks. The features distinguishing respiratory tract syndromes produced by influenza viruses from those produced by other viruses is the epidemic (an outbreak confined to one loca-tion) and even pandemic (an outbreak resulting from the emergence of a new virus to which the entire population has no immunity) nature of the disease and its mortality, which results in part from the pulmonary complications. In addi-tion, some patients develop nonpulmonary complications of influenza, including those related to CNS infection. Myalgia, which primarily affects the muscles of the back and the extremities, and headache are the most troublesome nonpulmonary symptoms and are related to the severity of the fever. Aching orbital pain that is worse during eye move-ments may occur. Many patients report tearing and a burning sensation in the eyes, which become watery and red. Influenza usually is a self-limited disease with minor re-spiratory and systemic manifestations. Nevertheless, about 10% of patients develop pulmonary complications of the disease that may be life-threatening (1704). These include primary influenzal viral pneumonia, secondary bacterial pneumonia, and croup (1705). In addition, patients who al-ready have pulmonary disease, such as those with chronic obstructive pulmonary disease or asthma, may experience an exacerbation of respiratory symptoms out of proportion to the other manifestations of the influenza. Also, transplant recipients are at increased risk of influenza viral pneumonia (1706,1707). 3230 CLINICAL NEURO-OPHTHALMOLOGY Rare patients with otherwise uncomplicated influenza, usually older patients and patients with pre-existing medical disease, develop nonpulmonary complications of the influ-enza virus infection. These complications are associated with an increased mortality from the infection, and they are re-sponsible for the bulk of deaths associated with influenza that are not related to primary viral pneumonia. The main nonpulmonary complications of influenza are myositis, myocarditis, pericarditis, toxic shock syndrome, and neuro-logic complications (1704,1708-1711). Ocular complica-tions also occur but are rare. Neurologic Complications Most patients with influenza have no neurologic symp-toms or signs, but a few develop one of several syndromes, including encephalitis, Guillain-Barre´ syndrome, Reye syn-drome, and transverse myelitis. Rare patients developing iso-lated cranial neuropathies have also been described. Rare patients with influenza, usually that caused by type B virus, develop a severe encephalitis or postinfectious en-cephalitis (acute disseminated encephalomyelitis) that can affect the cerebral hemispheres, brain stem, or both (52,1712-1716). The encephalitis, which initially may be mistaken for HSV encephalitis, occurs within 1 week of the onset of symptoms and usually is characterized by alterations in consciousness, mental deterioration, and seizures. Patients with brain stem involvement develop weakness, numbness, and multiple cranial neuropathies. Cerebellar dysfunction may occur, producing severe ataxia, dysarthria, and nystag-mus (1717). Neuroimaging studies in patients with influenza-associ-ated encephalitis may be normal or show changes consistent with diffuse cerebral edema. They may also show multifocal lesions that appear hypodense by CT scanning and hyperin-tense on T2-weighted MR images (1716,1718-1720). These lesions may be seen in the cerebral hemispheres, thalami and basal ganglia, cerebellum, and brain stem. SPECT studies performed in patients with encephalitis associated with influ-enza infection demonstrate areas of decreased uptake in the same location as the lesions seen on CT scanning and MR imaging (1720). These lesions may persist despite resolution of all neurologic signs and symptoms. Influenza-associated encephalitis may be fatal without ag-gressive supportive care, including assisted ventilation when needed. The role of antiviral therapy in the treatment of this condition is controversial. Guillain-Barre´ syndrome may occur after influenza A in-fection (1721,1722). The symptoms and signs are identical with those seen in both idiopathic Guillain-Barre´ syndrome and in Guillain-Barre´ syndrome associated with other viral and bacterial infections. It seems most likely that Guillain- Barre´ syndrome that occurs in association with influenza is caused not by specific infection with influenza virus but rather from some type of immunologic disturbance that af-fects the peripheral and central nervous systems. Reye syndrome may occur in patients with influenza and in asymptomatic patients with evidence of infection by influ-enza virus (380). Although this syndrome also may occur in patients with infections caused by a variety of other vi-ruses, most ‘‘associations'' of Reye syndrome with viral infection are isolated case reports and probably are fortuitous or associated with the use of aspirin. Only the associations of Reye syndrome with varicella infection and influenza virus infection seem to be causal. Indeed, 70-90% of patients who develop Reye syndrome have an antecedent upper respira-tory tract illness that in many cases is caused by influenza virus type A or B infection. Neurologic manifestations begin 4-6 days after the onset of typical symptoms and signs of influenza. Reye syndrome is characterized clinically by the acute onset of severe recurrent vomiting, restlessness, irritability, and a progressive decrease in consciousness over several hours. Raised intracranial pressure, often with papilledema, generalized hypertonia without focal signs, hyperventilation, sympathetic hyperactivity, and decorticate or decerebrate posturing then occur. Liver damage is manifested by hepato-megaly associated with abnormalities of liver function stud-ies. Neuroimaging studies show changes consistent with ce-rebral edema, with small ventricles and no evidence of a mass lesion. The CSF usually is normal, except for the in-creased intracranial pressure. EEG shows nonspecific dif-fuse slowing. Death results from cerebral edema and occurs in almost all untreated patients. Early recognition and prompt aggressive therapy to lower intracranial pressure and restore metabolic disturbances are associated with a mortal-ity of less than 20%. The pathophysiology of Reye syndrome is unknown. Var-ious mechanisms have been suggested, but none has been proven. Some authors report that children who receive aspi-rin for fever related to influenza have a higher incidence of Reye syndrome than do children who receive other antipyret-ics, but the mechanism by which aspirin supposedly causes the condition is unclear. Nevertheless, the American Acad-emy of Pediatrics recommends that an antipyretic agent other than aspirin be used for fever in children with influenza or varicella. Transverse myelitis can occur in association with influ-enza (1723). It usually develops within 1 week of the onset of initial manifestations of the infection and is characterized by numbness, weakness, and paresthesias of the extremities and trunk associated with bowel and bladder dysfunction. Such cases are not associated with optic neuritis (Devic syn-drome), and they usually are self-limited. Most patients re-cover, but some have persistent motor deficits, incontinence, or both. Engelhardt et al. (1724) described a boy who developed right-sided ptosis after otitis media when he was 2 years old. The ptosis resolved spontaneously. The child was then well until age 5, when he developed diplopia and ptosis associated with a fever and bronchitis. An examination at this time showed a right ptosis and limitation of upward gaze of the right eye consistent with paresis of the superior branch of the right oculomotor nerve (Fig. 57.63). A CT scan was normal. Serologic studies for viral antibodies were negative, except for evidence of antibodies to influenza A virus with a titer of 1 32. The child's CSF was entirely normal. The patient recovered completely without treatment, during VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3231 Figure 57.63. Superior division oculomotor nerve paresis associ-ated with influenza virus infection. The patient was a 5-year-old boy who reported double vision and was noted to have drooping of the right upper eyelid shortly after developing fever and upper respiratory tract symptoms. A, There is a mild right ptosis. B, There is limitation of elevation of the right eye on attempted upgaze in abduction (in the field of action of the right superior rectus muscle). C, Elevation of the right eye improves when the child attempts to look directly upward, indicating intact function of the right inferior oblique muscle. A complete evaluation revealed evidence of infec-tion with influenza A virus. The child eventually made a full recov-ery. (From Engelhardt A, Cedzich C, Ko¨mpf D. Isolated superior branch palsy of the oculomotor nerve in influenza A. Neuroophthal-mology 1989;9:233-235.) which time the anti-influenza A antibody titers decreased to below 1 4. Several authors have described patients who developed a partial oculomotor nerve paresis during an upper respiratory tract infection (1725-1727); however, serologic analyses for antibodies to specific viruses were not per-formed in any of these cases, so it is impossible to determine whether any of these cases were caused by influenza virus infection. Ocular Complications A retinopathy may occur in patients with influenza A in-fection (1728). Some patients have isolated macular edema, whereas others develop macular lesions characterized by shiny vesicular dots at the termination of a capillary. Other retinal lesions seen in patients with influenza A infection include absent foveal reflexes, darkening of the macular re-gion, and small hemorrhages (178). Nonretinal ocular abnor-malities seen in patients with influenza include iridocyclitis, interstitial keratitis, marginal corneal ulcers, and dacryoade-nitis (178). In addition to the neuro-ophthalmologic manifestations that may accompany the neurologic complications of influ-enza infection, a single case of bilateral neuroretinitis was reported by Knapp (1729). The patient was a previously healthy 32-year-old woman who began to lose vision in both eyes shortly after an attack of ‘‘grippe.'' She was examined 2 weeks after the onset of visual symptoms, at which time visual acuity was 15/200 OD and 20/200 OS, and visual fields showed bilateral central scotomas to green. Both optic discs were mildly swollen, and there was a ‘‘perfectly devel-oped star figure'' in the macula of the right eye. There was significant macular edema and haze but no exudate in the left eye. A lumbar puncture revealed a mild lymphocytic pleocytosis with an increased protein concentration. Tests for tuberculosis and syphilis were negative. There was a posterior ethmoid sinusitis, and a right ethmoidectomy was performed. Over the next several days, a star figure devel-oped in the left macula. The patient's visual acuity then slowly began to improve. Within 1 month after onset of symptoms, visual acuity had returned to 20/30 OU, both optic discs had become normal in appearance, and there were only ‘‘slight'' macular changes in both eyes. Diagnosis The diagnosis of influenza often is a clinical one, particu-larly when the infection occurs as part of an epidemic or pandemic. A rapid antigen detection test can be used to de-tect influenza type A virus (1730). Using this test, the virus can be identified within 15 minutes from a nasopharyngeal swab specimen. Confirmation of the diagnosis in cases of influenza caused by type B virus usually is made by isolating the virus from nasal swab specimens, throat swab specimens, nasal washes, or sputum (1704). About two thirds of positive cultures can be detected within 3 days of inoculation, the remainder within 5-7 days. Serologic tests designed to de-tect antibodies to influenza A and B viruses can also be used to diagnose influenza, but these take more time because paired serum specimens are required, one obtained during the acute phase of the disease and the other obtained during the convalescent phase about 10-20 days later (1705). The use of PCR to detect influenza virus RNA may be the most rapid and reliable method of diagnosing influenza (1705,1715,1717,1731). Treatment Many patients who develop influenza require no treatment because the disease is mild and transient. Others require only symptomatic care, consisting primarily of bed rest, antipy-retic agents, and fluid replacement. It is important that chil-dren and teenagers in particular avoid the use of aspirin and aspirin-containing products because of the risk of developing Reye syndrome. Patients with severe symptoms and signs, including patients with influenza-associated CNS disease, 3232 CLINICAL NEURO-OPHTHALMOLOGY may benefit from a number of drugs such as amantadine, rimantadine, and zanamivir (1704,1705,1732). Amantadine (1-adamantanamine hydrochloride) is a symmetric tricyclic amine that specifically inhibits the replication of influenza A viruses at low concentrations (1733) and thus is useful in the treatment of specific cases of influenza caused by type A virus. Unfortunately, amantadine only inhibits the replica-tion of influenza B virus at very high concentrations (1733), and it thus is less useful in influenza caused by that virus. Rimantadine is a structural analog of amantadine that has a similar mechanism of action against a similar spectrum of viruses (1704). Zanamivir is a sialic acid analog that selec-tively inhibits the influenza A and B virus neuraminidases. Direct administration of this drug to the respiratory tract is safe and reduces symptoms if begun early (1732). New antiviral drugs are constantly being developed and tested, however, and the physician caring for a patient with influ-enza may wish to consult an expert in infectious disease before prescribing any specific antiviral drug. Prognosis The overall risk of dying from influenza, regardless of the strain of virus responsible, is 1 in 5,000 to 1 in 10,000 per year (1704). The risk is higher among elderly persons and persons with underlying chronic systemic diseases, par-ticularly pulmonary and cardiac disease, than among normal young persons. Nevertheless, some strains of influenza virus are associated with a much higher mortality in both old and young persons. The 1918-1919 influenza pandemic, for ex-ample, caused 21 million deaths around the world, including over 500,000 in the United States alone (1734). Most patients with uncomplicated influenza, whether caused by type A or type B virus, recover completely within several weeks, regardless of treatment. Patients who develop secondary bacterial pneumonia also tend to recover when this complication is recognized early and treated appropri-ately. Patients with primary viral pneumonia, on the other hand, have a substantial morbidity and mortality, regardless of treatment, although both have declined significantly over the years with improvements in supportive care, particularly that provided in an intensive care unit. Patients who develop influenza complicated by myositis tend to recover slowly over several weeks to months without residua; however, pa-tients who develop cardiac complications of influenza, par-ticularly those with pre-existing cardiac disease, may have an increased risk of myocardial infarction and cardiac-in-duced death. Too few patients with influenza experience a toxic shock syndrome to make a dogmatic statement regard-ing their prognosis; however, it is safe to assume that this complication is associated with a substantial morbidity and mortality and should therefore be treated early and aggres-sively. With the exception of Reye syndrome, most neuro-logic complications of influenza also occur too rarely to de-termine a definitive prognosis. It is reasonable to assume that proper supportive care and careful monitoring can reduce the morbidity and mortality that may be associated with influ-enza- associated encephalitis, Guillain-Barre´ syndrome, and transverse myelitis. Reye syndrome, on the other hand, has a mortality of 10-40%, depending on the level of conscious-ness at diagnosis (1735). As already mentioned in an earlier section of this chapter regarding the development of Reye syndrome after varicella infection, general supportive mea-sures are crucial in patients with this condition. Careful at-tention to fluid and electrolyte balance is critical, as is as-sisted ventilation when needed. Intravenous glucose usually is required to correct hypoglycemia. Hemodynamic monitor-ing is also important. Because the major cause of death in such patients is cerebral edema, constant monitoring of intra-cranial pressure with therapy directed at aggressive lowering of it when necessary may be life-saving. Prevention The mainstay for the prevention of influenza since the late 1940s has been formalin-inactivated vaccines, which have efficacy rates of 67-92% (1704,1705,1736). Although the vaccines may produce localized, systemic, neurologic, or ocular side effects (1737-1739), the side effects usually are mild, even in elderly persons (1740). Nevertheless, sig-nificant adverse reactions to influenza vaccine occasionally occur. Encephalitis, meningoencephalitis, and myelitis can occur after influenza vaccination (1741-1744). Neurologic signs and symptoms in these cases generally occur within 1-2 weeks after vaccination. Some patients experience only headache, mild neck stiffness, and confusion without focal neurologic deficits. Others, however, have more extensive manifestations. The patient described by Wells (1741) was a 15-year-old boy who was said to have developed a ‘‘bulbar paralysis,'' and the patient described by Yahr and Lobos- Antunes (1742) was a 25-year-old woman who developed ataxia, slurred speech, and diplopia. Saito et al. (1743) de-scribed a 12-year-old boy who developed decreased con-sciousness, stiff neck, right hemiparesis, aphasia, papille-dema, and evidence of brain stem dysfunction 4 days after influenza vaccination. The patient described by Buchner et al. (1713) was a middle-aged man who developed an enceph-alomyelitis characterized by multiple cranial nerve pareses, ophthalmoplegia, and nystagmus. Most patients recover completely, although the patient described by Wells (1741) died 17 days after the onset of neurologic symptoms and signs, and the patient described by Saito et al. (1743) was said to have made an incomplete recovery. Hara et al. (1745) reported a case of bilateral anterior optic neuritis (papillitis) in a 10-year-old boy about 4 days after he received influenza vaccine. The patient was neurologi-cally well, but an EEG was abnormal. The patient's visual acuity eventually recovered. Hull and Bates (1746) described a woman who developed a bilateral anterior optic neuritis 2 weeks after receiving an influenza vaccination and who experienced a second episode of bilateral optic neuritis 17 days after she received another influenza vaccination the following year. We examined a 46-year-old woman in excel-lent general health who developed an acute unilateral ret-robulbar optic neuropathy 10 days after she received influ-enza vaccine. She had no previous or concurrent neurologic symptoms or signs, and MR imaging showed no abnormali- VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3233 ties. She was not treated, and her vision improved from 20/ 50 to 20/15 in the affected eye over about 6 weeks. It is possible that the retrobulbar neuropathy in this patient was related to the influenza vaccination. Kawasaki et al. (1747) described two patients who had permanent bilateral visual loss associated with evidence of a bilateral anterior optic neuropathy following influenza vac-cination. The pattern of visual loss, segmental optic disc swelling, and failure of visual recovery were more consistent with ischemia than inflammation, and the authors thus spec-ulated that an immune complex-mediated vasculopathy fol-lowing vaccination caused an anterior ischemic optic neu-ropathy in these patients. In 1976, a national immunization program was instituted to prevent the development of an influenza epidemic caused by a type A virus antigenically similar to the virus that had caused an epidemic in 1918, an epidemic that had been asso-ciated with an extremely high morbidity and mortality. As a result of intensive promotion of the program, 45 million persons received what was called the ‘‘swine flu'' vaccine (1704). During the first 4-6 weeks after immunization, an excess rate of Guillain-Barre´ syndrome occurred in vaccin-ees compared with persons who did not receive the vaccine (1748-1750). Although there was subsequent controversy regarding whether this apparent increase in cases of influ-enza vaccine-related Guillain-Barre´ syndrome was real, it was eventually determined that the risk of acquiring Guil-lain- Barre´ syndrome associated with the vaccine was at most 1 in 100,000, with a subsequent mortality of 5% and a neuro-logic morbidity of 5-10%. This was the only fatal complica-tion of the vaccine. A few patients given the ‘‘swine flu'' vaccine developed an encephalitis (1738,1751,1752), but all survived, and most recovered completely. Thus, the mortal-ity of vaccination with this vaccine was 1 in 2 million. Inter-estingly, subsequent influenza vaccinations have not been associated with an increased risk of Guillain-Barre´ syn-drome, nor with any other potentially fatal systemic or neu-rologic illness. Nevertheless, even if one assumes that the risk of death from any influenza vaccination is 1 in 2 million, the benefit-risk ratio for mortality is 200-400 times in favor of vaccination, because the risk of death related to complica-tions from influenza itself is 1 in 5,000 to 1 in 10,000 (1704). A number of cases of both unilateral and bilateral anterior and retrobulbar optic neuritis were said to have occurred as a result of the 1976 vaccination against swine influenza (1753-1756). In fact, in none of these cases was a causal association proved; indeed, one of the patients reported in the literature actually received the vaccine after the onset of visual loss. Some of these patients probably had demyelinat-ing optic neuritis; others may have had Leber hereditary optic neuropathy, although blood tests for the mitochondrial mutations were not available at the time. Although almost all immunizations are performed using inactivated vaccines, live influenza vaccines were developed primarily because inactivated vaccines for influenza, while effective, do not completely prevent infection. Numerous studies performed using a variety of volunteers, including young and healthy adults, children, the elderly, and the gen-eral population, suggest that live influenza vaccines not only are more effective in preventing influenza virus infection but also result in fewer and less severe symptoms in those who become infected and are associated with minimal reac-tions (1757,1758). Chemoprophylaxis is a viable alternative to vaccination for prophylaxis against influenza. The efficacy of amanta-dine in preventing influenza ranges from 75% to 90% in various studies and is thus similar to vaccination (1705, 1759,1760). In addition, its effectiveness seems to be addi-tive to that of vaccination. Dolin et al. (1761) compared the prophylactic effects of both amantadine and rimantadine with placebo. These investigators found no difference be-tween amantadine and rimantadine; both were significantly more effective in preventing clinical influenza than placebo. The major difference between the two drugs was a lower incidence of toxic side effects with rimantadine. Other inves-tigators agree that rimantadine is well tolerated and more effective than placebo in preventing clinical influenza (1762). Thus, it would seem that rimantadine, rather than amantadine, is the drug of choice for chemoprophylaxis against influenza infection either as the only method of pro-phylaxis or in combination with vaccination. Surveillance for amantadine- and rimantadine-resistant influenza virus strains, however, is necessary. We anticipate that new drugs will become available for influenza chemoprophylaxis in the near future. PARAMYXOVIRIDAE The paramyxoviruses once were considered to belong to the family Myxoviridae; however, they were subsequently separated from the orthomyxoviruses because their genomes are not segmented, as are the genomes of the orthomyxovi-ruses, and because they use a molecular strategy for both gene expression and replication that more closely resembles that of the rhabdoviruses than that of the orthomyxoviruses (1630,1763). There are three genera in the family Paramyxoviridae: Morbillivirus, Paramyxovirus, and Pneumovirus (1630). All three genera contain viruses that produce human diseases of neuro-ophthalmologic significance. The genus Morbillivirus contains the rubeola virus, which produces both measles and subacute sclerosing panencephalitis. The genus Paramyxovi-rus contains both parainfluenza viruses that produce human respiratory tract infections and, occasionally, meningitis. It also contains the mumps virus, which produces mumps and its neurologic and ocular sequelae, and the Nipah virus, re-sponsible for outbreaks of fatal encephalitis in Malaysia and Singapore. The genus Pneumovirus contains the respiratory syncytial virus (RSV). Although this virus most often pro-duces pneumonia and bronchiolitis in infants and children and the common cold in both children and adults, it may also play a role in the development of CNS disease in both adults and children. In the sections that follow, we discuss measles virus, mumps virus, Nipah virus, and respiratory syncytial virus, as well as the human diseases of neurologic and visual significance that these viruses produce. Morbilliviruses The genus Morbillivirus contains several animal viruses, including the virus that causes distemper in dogs and the 3234 CLINICAL NEURO-OPHTHALMOLOGY rinderpest virus that causes a similar disease in cattle. The equine morbillivirus can cause a fatal acute respiratory ill-ness in both horses and humans (1764,1765), and one case of fatal encephalitis caused by this virus was reported by O'Sullivan et al. (1666) in a 35-year-old Australian man to whom the virus was transmitted from an infected horse. Nevertheless, the most important morbillivirus from a neuro-ophthalmologic standpoint is the rubeola virus. Characteristics Each virion of the rubeola (from the Latin rubeus, mean-ing ‘‘red'') or measles virus consists of an outer envelope with short surface projections and an inner nucleocapsid that is a coiled helix of protein and single-stranded RNA (1767). The virus contains six structural proteins, three of which are complexed with RNA and three of which are associated with the viral envelope (1767). The three proteins complexed with the viral genome are called the N (nucleocapsid) protein, the P (phospho) protein, and the L (large) protein. The envelope contains the M (matrix) protein-a nonglycosylated protein associated with the inner part of the lipid bilayer-and two glycoproteins designated H and F (1767). The M protein is thought to play a role in viral assembly. The H glycoprotein is responsible for the adsorption of the virus to receptors on the host cell, the first step in infection, and it also is the antigen that mediates hemagglutination (hence, its designa-tion), the major serologic test for measuring antibody to the virus. The F glycoprotein is responsible for the membrane fusion of the virus and host cell (hence, its designation), penetration of the virus into the cell, and hemolysis, a prop-erty that also is used in measuring antibodies to rubeola virus. Humans are the only natural host for the rubeola virus. Acute human infection with the virus produces a disease called rubeola or measles. A second disorder, subacute scle-rosing panencephalitis, occurs years after measles infection and is also related to viral infection. Measles Measles occurs throughout the world, but its incidence has decreased greatly since the institution of widespread vac-cination. Before the availability of a measles vaccine, 200,000-500,000 cases of measles were reported annually in the United States. Subsequently, the number of cases dropped significantly, reaching a low of 1,497 cases reported to the Centers for Disease Control in 1983 (an incidence rate of 0.6%), with most of these cases occurring in previously vaccinated persons 5-19 years old (1767). The number of cases then steadily rose. Most of the cases occurred in unvac-cinated preschool children and a smaller percentage in vacci-nated school-age children (1768), and it became clear that the major reason that measles had not been completely elimi-nated from the United States was failure to immunize all persons who qualify for vaccination, despite the enactment of laws requiring proof of immunity to measles for entry into school. An analysis of the geographic distribution of measles in the United States from 1980 through 1989 indi-cated that the major foci for recurrent measles transmission in the United States were few and included large metropoli-tan areas, especially those with a large population of Hispan-ics (1768). Other less common reasons included primary vaccine failure and importation of measles to the United States from other countries. In any event, beginning in 1990, a concerted effort was made to inform parents of the need to vaccinate their children against measles. This resulted in a decrease in the number of reported cases in the United States and suggests that the resurgence of measles that oc-curred in the United States from 1984 through 1989 has ended. EPIDEMIOLOGY Measles is spread by contact with droplets from the respi-ratory secretions of infected persons. The virus remains in-fective in such droplets for several hours, especially when there is low relative humidity, and this may account for the increased incidence of the disease in the winter (1767). Pa-tients with measles are most infectious during the late pro-dromal phase of the illness, when cough and coryza are max-imum. CLINICAL MANIFESTATIONS The clinical manifestations of measles depend in part on whether the patient has any immunity to the measles virus. Patients with no immunity develop typical measles, whereas patients with partial passive immunity develop a modified form of the disease. Patients who are immunized against measles with a vaccine that produces only short-term immu-nity develop an atypical form of measles. In addition, al-though most patients have no complications from the disease and recover without sequelae, some develop severe and life-threatening complications. The incubation period of typical measles is 10-14 days, although it may be somewhat longer in adults than in chil-dren (1767). A prodromal phase lasting several days then occurs and is characterized by malaise, fever, anorexia, con-junctivitis, and respiratory symptoms, such as cough and coryza, that may suggest a severe upper respiratory tract infection. Toward the end of the prodromal period, Koplik spots usually appear. These spots, which are pathognomonic of measles, are blue-gray specks on a red base. They usually develop on the mucosa opposite the second molars, but the entire mucous membrane of the mouth may be affected in severe cases. The spots persist for several days and then slough as an external rash appears. Koplik spots are reported to occur in 30% of patients with otherwise typical measles in some series (1769). The rash of measles, which occurs in most but not all patients with the disease, is erythematous, maculopapular, and nonpruritic. It usually begins on the forehead and behind the ears, then progresses downward to affect the neck, trunk, upper extremities (including the palms of the hands), but-tocks, and lower extremities (including the soles of the feet), all within 3 days. It becomes confluent as it progresses, espe-cially on the face and neck. The rash lasts about 5 days, with the patient becoming most ill during its first or second day. It then starts to clear, and the clearing also progresses from head to foot. During this time, the affected skin (except the VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3235 palms and soles) may desquamate, but the fever abates and the patient begins to feel better. The entire illness, when uncomplicated, lasts only 7-14 days. An extremely mild form of measles may develop in per-sons with some degree of passive immunity to the rubeola virus, such as infants with remaining passively acquired ma-ternal antibodies to measles virus and susceptible persons who previously received gamma globulin after an exposure to measles. The manifestations of measles in such persons are extremely variable, and certain typical phenomena, in-cluding the prodromal period, Koplik spots, and even the rash, may never occur (1767). An atypical attack of measles may occur in patients who are vaccinated with any vaccine that confers only short-lived immunity. From 1963-1967, for example, about 1.8 million persons in the United States were given a formalin-inacti-vated measles vaccine. It was later discovered that this par-ticular vaccine conferred only short-term immunity and that patients immunized with this vaccine did not develop anti-bodies against the viral F protein, as occurred with other vaccines. When these patients were exposed to the natural virus, they often developed a type of delayed hypersensitiv-ity reaction that could be quite severe (1770). Preferential stimulation of type 1 CD4 cells by inactivated virus vac-cine is hypothesized to play a role in the development of atypical measles (1771). After an incubation period of 1-2 weeks, these patients experienced fevers, headaches, abdom-inal pain, myalgias, and cough. They did not develop Koplik spots, but they did develop a diffuse rash that could be ery-thematous, maculopapular, vesicular, or petechial. The rash started not on the forehead, as occurs in typical measles, but on the extremities, from which it spread inward. Many of these patients subsequently developed pneumonia, and some experienced CNS complications, such as encephalomyelitis (1772). Most patients who develop measles have an uncompli-cated benign illness, but some develop severe and potentially life-threatening complications. The most common complica-tions of measles are otitis media, pneumonia, keratitis and corneal ulceration related to associated xerophthalmia lead-ing to blindness (1772a), and neurologic disease; however, other complications, including those that affect the retina and optic nerve can occur. Otitis media is the most common complication of measles. It occurs in 7-18% of all cases (1773). The pathogenesis of this complication is unclear. Uncomplicated measles can affect the respiratory tract, producing cough and coryza. Most patients then improve spontaneously; however, about 6% develop severe pneumo-nia that may be caused either by direct viral invasion of the lungs or by bacterial superinfection. Pneumonia accounts for about 60% of infant deaths in the setting of measles (1767). Viral invasion of the CNS may be a common feature in uncomplicated measles, because about 50% of patients with measles but without neurologic manifestations have EEG disturbances (1774,1775), and one third show a pleocytosis in their CSF (1776). Some children who experience appar-ently uncomplicated measles have subsequent, although mild, disturbances of behavior (1777), and 1 in 1,000 to 1 in 2,000 patients with measles develop overt clinical signs of CNS disease. Individual cases of transverse myelitis, polyneuritis, and acute hemiplegia occur, but by far the most common neurologic manifestations of measles, particularly in nonimmunized populations, are an acute encephalitis or encephalomyelitis that develops during the infection, and acute disseminated encephalomyelitis (ADEM) that devel-ops during convalescence (164,1778-1783). Acute measles encephalitis usually begins between the 4th and 11th days of the disease, at a time when the tempera-ture has returned almost to normal and the rash has begun to fade. In the diffuse form of the disease, the patient becomes drowsy, reports a headache, and vomits. The pupils become dilated, and there are diffuse muscular twitchings. Evidence of meningeal irritation, such as nuchal rigidity and a positive Kernig sign, then develops. MR imaging may show multifo-cal abnormalities in the cerebral hemispheres with swelling of the cortex, involvement of the basal ganglia, and diffuse atrophy (1781,1782). Acute measles encephalitis may present as a monofocal process. Patients with this form of encephalitis may develop an acute hemiparesis, aphasia, or even a homonymous visual field defect. For example, Walsh and Hoyt (1784) described a 4-year-old girl who developed measles. Ten days after the onset of the illness, she developed a right hemiplegia and lost the ability to speak. The hemiplegia resolved within 2 months; however, speech returned very slowly, and for sev-eral years she used only a few words. At age 11, an examina-tion revealed that she had a complete right homonymous hemianopia. The CSF in patients with acute measles encephalitis or encephalomyelitis may be normal. More often, however, there is a mild lymphocytic pleocytosis associated with an increased concentration of protein and a normal glucose con-centration. The intracranial pressure may be normal or in-creased in such cases. Patients with otherwise typical measles-associated en-cephalitis also may develop signs and symptoms of spinal cord damage, such as paraparesis, sensory disturbances, and bowel or bladder dysfunction (1772,1785,1786). Such pa-tients have an encephalomyelitis rather than an encephalitis. The mortality of acute measles encephalitis and encepha-lomyelitis is as high as 15% in some countries, regardless of treatment (1778). In addition, 25-60% of survivors have severe neurologic sequelae, including mental retardation, seizures, severe disorders of behavior, deafness, hemiplegia, and paraplegia (345,1778). Some patients have a complete and permanent homonymous hemianopia (1784), although permanent cortical blindness is rare, if it occurs at all. One of the patients described by Miller (364) had a persistent but mild abducens paresis. Ford and Guild (1787) described three patients who had precocious puberty after an episode of measles encephalitis, presumably from damage to the hy-pothalamus. One of these patients also experienced bilateral retrobulbar optic neuritis (discussed later). The majority of cases of CNS involvement related to mea-sles are caused by ADEM (1788). The condition develops during convalescence from otherwise uncomplicated mea-sles and is characterized by recurrent fever, headache, and 3236 CLINICAL NEURO-OPHTHALMOLOGY an alteration in consciousness that may progress to coma. Seizures are common, occurring in almost 50% of patients. There often is papilledema or at least congestion of the optic discs, and some patients develop unilateral or bilateral abdu-cens nerve pareses caused by increased intracranial pressure. Other findings include involuntary movements, hemiparesis, homonymous visual field defects, and both formed and un-formed visual hallucinations.MRimaging reveals multifocal abnormalities in the brain and spinal cord (1788). Some cases of ADEM are characterized only by cerebellar dysfunction. Affected patients develop sudden ataxia, loss of muscle tone, scanning speech, nystagmus, intention tremor, and typical cerebellar gait. Walsh and Hoyt (1784) described a 2-year-old girl who developed measles that was complicated by this form of encephalitis. The child experi-enced seizures and exhibited gross ataxia of all extremities. She gradually developed spasticity of the left arm and leg. She eventually improved, but she had persistent mental defi-cits, ataxia, and seizures. Figure 57.64. Pathology of measles encephalitis and encephalomyelitis. A, Coronal section through the brain at the level of the internal capsule shows multiple foci of perivascular demyelination, together with a diffuse loss of myelin. Kultschnitzky myelin stain. B, Histologic section in another case shows demyelination associated with perivascular and parenchymal infiltration of the brain. Luxol fast blue, 150. C, Another histologic section shows loss of myelin around a perivascular inflammatory cuff. Heidenhain preparation, 160. D, Histologic section through the thoracic spinal cord in a patient with postinfectious encephalomyelitis from measles. Note multiple, radiating perivenular foci of demyelination. Kultschnitzky myelin stain. (From Raine CS. Demyelinating diseases. In: Davis RL, Robertson DM, eds. Textbook of neuropathology. 2nd ed. Baltimore: Wil-liams & Wilkins, 1991 535-620.) The pathology of measles-associated ADEM is typical (1789,1790). On gross examination, petechial hemorrhages may be visible on the surface of the brain and spinal cord. The weight of the brain is often increased from edema and swelling of the cortical gyri. Coronal section reveals conges-tion of blood vessels, particularly in the white matter. Nar-row gray zones can sometimes be traced around small ven-ules in the white matter of the brain and the penetrating vessels of the spinal cord. The distinctive microscopic feature of measles-associated ADEM is a significant inflammatory response associated with perivascular demyelination (1789) (Fig. 57.64). The extent and severity of the inflammation correlate with the duration of the disease. Longer survival is associated with more quiescent lesions that have a morphology similar to that seen in patients with chronic multiple sclerosis. The inflammatory response occurs around small to medium-sized venules within the white matter, particularly but not exclusively in the pons. The perivascular cuffing occurs VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3237 around scattered vessels, with individual lesions ranging in size from 0.1-1.0 mm in diameter. Small lesions often coa-lesce to form larger areas of inflammation. The infiltrate is primarily composed of lymphocytes, plasma cells, and large mononuclear cells that are interspersed with occasional eo-sinophils and fat-laden macrophages called gitter cells. PMNs are present in severe cases. Beyond the perivascular infiltrate are narrow rims of demyelination associated with scattered inflammatory cells. Hypertrophic astrocytes and fibrillary gliosis are present within these narrow sleeves of demyelination and in the adjacent parenchyma. Fat-laden microglial cells abut normal white matter around the lesions, a phenomenon called ‘‘wall-formation.'' As lesions become older, increasing numbers of macrophages are found in peri-vascular spaces, and inflammatory cells decrease in number. Patients with measles-associated ADEM frequently show inflammation around both meningeal veins and the vessels penetrating the spinal cord. The meningeal inflammation is associated with narrow zones of subpial demyelination, whereas the inflammation that surrounds the penetrating ves-sels is associated with radiating sleeves of myelin loss. The pathogenesis of acute measles encephalitis and en-cephalomyelitis probably is caused by direct viral invasion of the CNS, because virus particles can be detected in brain specimens from fatal cases. For example, in five cases of acute fatal measles, endothelial cell infection was demon-strated by in situ hybridization and PCR techniques (1791). ADEM, however, appears to be caused by an immune-me-diated attack on CNS myelin (1789,1790). Whether this de-myelination is the result of a direct and specific attack or whether myelin and oligodendroglia are damaged from an excess of locally produced immunologic factors, such as cytokines, that are generally hostile to myelin remains to be shown. One hypothesis suggests that measles causes enceph-alomyelitis by preferential long-term activation of Th 2 CD4 cells, thus triggering an immune response (1771). A remarkable case of measles virus infection associated with coronary arteritis and systemic vasculitis was reported by Takano et al. (1792). The patient was a 2-year-old girl who developed a high fever associated with hepatomegaly and lymphadenopathy. She was treated with systemic antibi-otics and corticosteroids and initially improved; however, she subsequently worsened, developed severe pneumonia, and died 8 months after the onset of symptoms. Postmortem examination revealed severe pneumonia, generalized lym-phadenopathy, hepatomegaly, splenomegaly, and aneurys-mal dilation of the coronary arteries associated with cardiac hypertrophy. Histopathologic examination of the coronary arteries revealed marked thickening of the intima with infil-tration of lymphocytes, plasma cells, macrophages, and giant cells that contained both intranuclear and intracytoplasmic eosinophilic inclusions surrounded by a halo. A similar infil-trate was seen in other vessels, including the aorta, common iliac arteries, splenic arteries, and gastroduodenal arteries. Electron microscopic examination of affected vessels re-vealed that the intracellular inclusions were morphologically consistent with measles virus, and immunofluorescent anti-body studies confirmed that the structures were measles virus nucleocapsids. The authors suggested that the patient had experienced a severe disseminated infection by measles virus that had produced a systemic immune-mediated vascu-litis. Optic neuritis occurs in a few patients with measles (1793-1795). Visual loss may occur from 6 days before the onset of the rash (1796) to 1 month after its development (1797,1798). Loss of vision usually is bilateral, although Srivastava and Nema (1799) reported a case of unilateral visual loss in an 8-year-old child. In some cases, vision is lost during a typical attack of measles encephalitis or enceph-alomyelitis that may be quite mild or severe (1784, 1797,1798). In others, optic neuritis is the only or the major finding in patients with otherwise uncomplicated measles (1784,1795,1799). Walsh and Hoyt (1784), for example, de-scribed a child with bilateral retrobulbar neuritis caused by measles. The patient was 8 years old when he developed measles. He lost vision in both eyes 6 days after the onset of the disease. The patient had bilateral central scotomas and normal-appearing optic discs. He had no neurologic symp-toms or signs. His visual acuity gradually improved over the following 6 weeks. The degree of visual loss in measles-associated optic neu-ritis usually is severe, ranging from complete blindness to hand motions vision. The optic discs may appear normal or swollen. In some cases, there is associated edema of the retina in the posterior pole, as if there were a central retinal artery occlusion, and this may lead to a severe pigmentary retinopathy (discussed later). In other cases, however, there are no associated retinal changes. Most patients recover use-ful vision in both eyes, and some even regain 20/20 vision. In many cases, the appearance of the optic discs returns to normal as swelling resolves in patients with anterior optic neuritis or remains normal throughout the course of the vi-sual loss in patients with retrobulbar neuritis; however, in other cases of both anterior and retrobulbar neuritis associ-ated with measles, the optic discs develop pallor that may be mild or severe. Some patients with measles in whom acute visual loss occurs eventually develop a severe, usually bilateral, pig-mentary retinopathy with optic atrophy and narrowed retinal arterioles. In most cases, the pigmentary retinopathy resem-bles that of retinitis pigmentosa (178,1800-1804), whereas in other cases, the appearance is more like the ‘‘salt-and-pepper'' appearance seen in children with congenital mea-sles infection (1805) or rubella retinopathy (discussed later). Most patients present with bilateral optic disc swelling asso-ciated with edema of the retina, suggesting a partial occlu-sion of the central retinal artery. Over weeks to months, there may be some improvement in vision, but the visual fields usually become markedly constricted, and there is persistent night blindness. The ocular fundi evolve through a stage of ‘‘salt-and-pepper'' pigmentary retinopathy associated with optic atrophy, at which point the process may stop. In most cases, however, the fundus appearance continues to deterio-rate until there is severe, diffuse pigment degeneration of the retina with bone spicule deposits and markedly narrowed retinal arteries. The electroretinogram (ERG) in such pa-tients is either extinguished or markedly abnormal. In some cases, the initial ophthalmoscopic findings are 3238 CLINICAL NEURO-OPHTHALMOLOGY subtle. Haydn (1806) described a 7-year-old girl who sud-denly lost vision in both eyes 5 days after the onset of the exanthem of measles. Examination at this time revealed vi-sual acuity of light perception in each eye. Both pupils re-acted sluggishly to light. Ophthalmoscopic examination was unremarkable, and a diagnosis of retrobulbar neuritis was made. Within a few days, however, the optic discs became swollen and hyperemic, the retinal arteries became nar-rowed, and small pigmented spots began to appear through-out the fundi adjacent to the narrowed retinal arteries. The patient rapidly developed a severe pigmentary retinopathy and optic atrophy in both eyes associated with a flat ERG. She remained irreversibly blind despite treatment with both antibiotics and systemic corticosteroids. Walsh and Hoyt (1784) described a 14-year-old girl who experienced an attack of measles when she was 4 years old. She lost vision completely in both eyes 5 days after the onset of the rash. After a month, the vision improved in the right eye. The patient never had any neurologic symptoms or signs. She was examined 8 years later, at which time visual acuity was 20/200 OD and hand movements OS. There was marked constriction of both visual fields, with only a small nasal paracentral island of vision in both eyes. The patient had a small-amplitude conjugate nystagmus that sometimes was purely torsional and sometimes had both horizontal and torsional components. Extraocular movements were full, but there was a small left sensory exotropia. The right optic disc was slightly pale, but the left optic disc seemed normal in color. Both fundi showed severe pigmentary retinopathy. The pathogenesis of the pigmentary retinopathy that occurs in association with otherwise uncomplicated measles is un-clear. Trub (1807) described a 23-year-old patient who pre-sented with bilateral punctate keratitis without conjunctival reaction 10 days after the onset of measles. A late immuno-logic reaction was assumed to be the etiology. Measles in Immunocompromised Patients. Other-wise typical measles may have a fatal outcome in patients who are immunocompromised from drugs or disease, partic-ularly in patients with impaired cell-mediated immunity. Such patients frequently develop progressively severe pul-monary insufficiency over the course of an otherwise un-complicated illness. Immunocompromised patients, espe-cially patients with leukemia, lymphoma, and AIDS, are also at risk to develop a delayed acute or subacute progressive encephalitis called measles inclusion body encephalitis (MIBE) or subacute measles encephalitis (SME) (1808- 1815). The condition develops after an incubation period of 5 weeks to 6 months. Seizures usually are the initial mani-festation, followed closely by hemiplegia or hemiparesis, slurred speech, stupor, and eventually coma (1816). The dis-order is almost always fatal, with death occurring 1 week to 2 months after the onset of neurologic manifestations (1817,1818). Nevertheless, early diagnosis and aggressive treatment may be associated with survival (1810). The external appearance of the brain in cases of SME may be normal, and it certainly does not show the severe swelling and necrosis associated with most of the acute viral encepha-litides (1170,1171). Some brains show focal abnormalities, such as softening or discoloration in the cerebral cortex or white matter. The diagnostic feature of SME is eosinophilic, usually intranuclear, inclusion bodies in neurons and oligo-dendrocytes, and it is for this reason that the condition is often called measles inclusion body encephalitis. Collections of these bodies may be remarkably focal and unassociated with any cellular reaction, although in some cases they are widespread throughout the white and gray matter of the brain. Electron microscopic examination of these structures shows that they are nucleocapsids; however, the viral bud-ding that is normally seen in cells that are acutely infected by measles virus is not present (1816). These pathologic features are similar to those seen in patients with subacute sclerosing panencephalitis (discussed later), except that peri-vascular infiltration by T and B lymphocytes is minimal or absent in SME (1809). PATHOGENESIS Measles virus infects by invading the respiratory epithe-lium at any point from the nose to the bronchioles of the lungs (1767). Once the virus invades the respiratory epithe-lial cells, replication of virus occurs and is followed by a primary viremia, during which the virus spreads via PMNs to the mononuclear-phagocytic (reticuloendothelial) system. These cells subsequently become necrotic, releasing more virus and resulting in reinvasion of PMNs and a secondary viremia. When the secondary viremic phase of measles oc-curs, the entire respiratory mucosa becomes affected, and severe cough and coryza occur. Damage to the mucosa also predisposes to both further damage to the respiratory tract by the virus and secondary bacterial pneumonia. Within a few days after generalized damage to the respira-tory tract epithelium, Koplik spots appear and are followed shortly thereafter by the typical measles rash. These manifes-tations coincide temporally with the appearance of antibody to measles virus in the serum and the termination of commu-nicability of the disease. It is therefore postulated that the mucous membrane and skin manifestations of measles are actually hypersensitivity reactions of the host to the virus. DIAGNOSIS The diagnosis of measles usually is made on the basis of the clinical presentation and usually is straightforward. In difficult cases, especially those with atypical presentations and those modified by partial immunity (discussed earlier), serologic testing can be helpful (1769). Total antibody to rubeola virus appears a few days after the appearance of the rash, peaks within 4 weeks, and then declines. The IgM antibody component peaks just after the rash disappears and is present for about 6 weeks, whereas the IgG component can be detected at low levels throughout life. ELISA tests are one of the most common serologic methods used to detect antibody in patients with presumed measles (1770); how-ever, molecular genetic techniques, using PCR and nucleic acid probes, are rapidly replacing all serologic tests for mea-sles, and such tests may permit early and rapid diagnosis of all forms of the disease, including SME (1781,1809,1819). VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3239 TREATMENT Measles is a benign, self-limited disease in most persons; however, some patients require supportive care. Antipyretics are often useful, but aspirin and aspirin-containing products should be avoided in children because of the association of these drugs with Reye syndrome. Neither Koplik spots nor the rash of measles usually requires treatment. Careful moni-toring of pulmonary function is important, particularly in infants and the elderly. Patients who develop pulmonary dis-tress should be evaluated for evidence of secondary bacterial infection and treated aggressively with antibiotics, pulmo-nary toilet, or both. Measles pneumonitis may respond to treatment with intravenous ribavirin (1820). There is no spe-cific antiviral treatment for acute measles-associated enceph-alitis, but systemic steroids may be useful in measles-associ-ated ADEM. Supportive care with monitoring of intracranial pressure and neurologic status, ideally provided in an inten-sive care unit, may be life-saving. As noted previously, most immunocompromised patients who develop the syndrome of SME die within 2 months of the onset of the condition. Early diagnosis and treatment of the condition with antiviral drugs may, however, result in survival with few or no sequelae (1809). PREVENTION AND THE COMPLICATIONS OF VACCINATION Vaccination is the major method of preventing measles. The progenitor measles strain for all current measles vac-cines was isolated from a patient named Edmonston. A for-malin- inactivated vaccine derived from this strain was used from 1963 to 1967, but, as noted earlier, the vaccine con-ferred only short-term immunity, and many patients who Figure 57.65. Oculomotor nerve palsy after measles immunization. The patient was a 17-month-old boy who developed drooping of the right upper eyelid associated with irritability and vomiting 2 weeks after receiving a measles vaccination consisting of Edmonston vaccine. A, The patient has a complete right oculomotor nerve palsy with involvement of the pupil. An evaluation gave normal results. B, Five days later, the ptosis is beginning to improve. The right eye remains exotropic. The condition eventually resolved completely. (From Chan CC, Sogg RL, Steinman L. Isolated oculomotor palsy after measles immunization. Am JOphthalmol 1980;89 446-448.) received this vaccine eventually developed ‘‘atypical'' mea-sles (discussed previously). A live attenuated form of the original strain, called ‘‘Edmonston B,'' was developed shortly thereafter and was administered throughout the world from 1963 through 1975. Protection from measles was better with this live virus vaccine, but side effects, such as fever and rash, were common, and immune globulin had to be given along with the vaccine to protect against these un-wanted effects. Chan et al. (1821) described a 17-month-old boy who became irritable and had an episode of vomiting about 2 weeks after being vaccinated with what was probably Edmonston B vaccine. Twenty-four hours later, he devel-oped a complete right oculomotor nerve paresis affecting the pupil (Fig. 57.65). An extensive evaluation that included a CT scan and a lumbar puncture was unremarkable. The paresis began to resolve within 1 week after onset, and it had completely resolved within 2 months. Although this could have been a case of ophthalmoplegic migraine, there was no history of migraine in the patient's family, and the patient had no other similar episodes over the next 14 months. Strains of attenuated virus other than those described ear-lier but nevertheless derived from the original Edmonston strain were subsequently developed that seemed to be associ-ated with fewer side effects and longstanding immunity, and combination vaccines against measles, mumps, and rubella (MMR) have been available since 1971 (1822). Complica-tions from these vaccines, particularly the Moraten strain, are rare and generally mild, with most of the side effects apparently related to the mumps vaccine component (1823). Nevertheless, the use of high-titer measles vaccines is asso-ciated with an increased mortality among recipients, and 3240 CLINICAL NEURO-OPHTHALMOLOGY such vaccines generally are no longer given. In addition, 5-15% of recipients develop a fever 5-11 days after vacci-nation with most standard measles vaccines, and about 5% of patients develop a transient rash. Thrombocytopenic purpura also occurs in rare patients after vaccination with a combina-tion vaccine (1824), presumably from the effects of the mea-sles virus itself. In addition, neurologic and ophthalmologic complications may occur in patients who receive either a pure measles vaccine or a combined vaccine that includes attenuated measles virus as one of its components. Cases of encephalitis (including SME), meningitis, and myelitis have been reported after immunization with the MMR vaccine (1750,1823-1829), as have parkinsonism (1830), unilateral and bilateral hearing loss (1831-1833), and recurrent abducens nerve paresis (1834). Despite these reports, a study of 535,544 children aged 1-7 years who were vaccinated with the MMR vaccine found no cases of encephalitis, aseptic meningitis, or autism within the desig-nated risk period, suggesting either no association or a mini-mal association of the MMR vaccine with neurologic se-quelae (1835). Unilateral or bilateral hearing loss may occur after a mea-sles vaccination (1833-1835). In some cases, the hearing loss is associated with evidence of an encephalopathy; in others, it occurs as an isolated phenomenon. Seizures occur in some children after a measles vaccina-tion (1808). The seizures usually coincide with a postvacci-nation fever and resemble the typical ‘‘febrile seizures'' seen in nonvaccinated children with high temperatures from a variety of causes (1835a). They occur more frequently in children with a family history of seizures and in children Figure 57.66. Bilateral optic neuropathy after immunization with trivalent measles, mumps, and rubella (MMR) vaccine. The patient was a 6-year-old boy who developed decreased vision associated with pain on movement of the eyes 18 days after receiving trivalent MMR vaccine. Visual acuity was 20/25 OD and counting fingers at 1 foot OS. A left relative afferent pupillary defect was present. A, The right optic disc is swollen. B, The left optic disc is swollen. An evaluation showed no abnormal findings. The patient was given systemic corticosteroids and eventually experienced improvement in vision to 20/ 20 OU associated with disappearance of optic disc swelling. (From Kazarian EL, Gager WE. Optic neuritis complicating measles, mumps, and rubella vaccination. Am JOphthalmol 1978;86 544-547.) who previously experienced unrelated seizures. Seizures as-sociated with measles vaccination are self-limited and be-nign and occur at a sufficiently low rate that vaccination against measles should not be withheld on the basis of this potential complication. A case of bilateral, simultaneous, anterior optic neuritis that was temporally related to administration of trivalent MMR vaccine was reported by Kazarian and Gager (1836). The patient was a 6-year-old boy who developed acute loss of vision in the left eye associated with left orbital pain on left lateral gaze and general malaise 18 days after vaccina-tion. An examination revealed visual acuity of 20/25 OD and finger counting at 1 foot OS. There was a left-sided RAPD. Both optic discs were swollen, and scattered peripap-illary splinter hemorrhages were present in the left ocular fundus (Fig. 57.66). An evaluation, including skull x-rays, CT scan, and lumbar puncture, showed no abnormal find-ings. The patient was given oral prednisone and experienced gradual improvement in vision. Visual acuity eventually re-turned to 20/20 OU, although the patient had a persistent left RAPD, an inferior defect in the visual field of the left eye, and mild pallor of both optic discs. Even if this attack of bilateral asymmetric anterior optic neuritis was, in fact, causally related to the trivalent vaccine received by the pa-tient 18 days earlier (and we believe it was), it is unclear what component of the vaccine triggered the attack. Optic neuritis can occur in the setting of measles (discussed earlier) and mumps (discussed later), so one may assume that either virus could have induced the attack in this patient. Retinopa-thy following MMR vaccination has also been described (1837). VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3241 Some investigators believe that there is an association be-tween measles vaccination and Guillain-Barre´ syndrome. However, da Silveira et al. (1838) analyzed data on 2,296 cases of Guillain-Barre´ syndrome with respect to an associa-tion with measles vaccination and found no statistically sig-nificant association. These authors concluded that if there were any causal relation, the number of cases of Guillain- Barre´ syndrome caused by measles vaccination was so small that it would be inappropriate to withhold the vaccine. It is clear that vaccination against measles should be per-formed early in life, despite the occasional adverse reactions that occur after vaccination (1808), although the age at which children should be vaccinated is controversial. Nevertheless, the potential complications of measles are far more common than are the potential complications of the vaccines, and the efficacy in preventing measles with currently available vaccines is extremely high. Although vaccine failure can occur even after the two-dose schedule currently recom-mended, the major reason that measles continues to occur throughout the world is failure to vaccinate, rather than vac-cine failure (1839,1839a), and we agree with others that ef-forts to eliminate measles and its complications should be directed toward establishing comprehensive vaccination pro-grams for preschool children who live in developing coun-tries or who live in developed countries but who are not offered or do not take advantage of existing programs (1767,1768,1839a). Subacute Sclerosing Panencephalitis Subacute sclerosing panencephalitis (SSPE) is a chronic progressive degenerative CNS disease that is caused by the measles virus but occurs years after measles infection. It occurs only in patients who have had measles. SSPE was first described in 1933 by Dawson, who called the condition ‘‘lethargic encephalitis.'' Later authors called it ‘‘Dawson's encephalitis'' or ‘‘subacute sclerosing leu-koencephalitis.'' Greenfield (1840) originated the term ‘‘subacute sclerosing panencephalitis'' to emphasize the damage to both white and gray matter of the brain caused by the disease. SSPE is similar in some respects to SME (discussed previ-ously), except that the asymptomatic period after the measles infection is much longer. In addition, patients who develop SME respond poorly to measles antigens, whereas patients with SSPE have a strong immune response to most measles virus proteins, except theMprotein (1810,1816,1841,1842). EPIDEMIOLOGY The incidence of SSPE in the general population is about 0.35 cases per million per year in the United States and about 1 case per million per year throughout the world (1808). Among persons who experience an attack of measles, the annual incidence of SSPE is 0.6-2.2 per 100,000 cases. SSPE usually develops in children, with the average age of onset about 9 years in most series; however, young adults may also be affected (164,1843-1850). Over 50% of these patients experienced typical measles before they were 2 years old. The mean incubation period thus is about 6-7 years. In the United States, there seems to be a higher preva-lence in Caucasians than in African-Americans or Hispanics, and the disease seems to develop more often in patients who live in rural areas, particularly in the Southeastern region, than in patients who live in large cities (1808). In South Africa, most cases occur in native Africans (1843). CLINICAL MANIFESTATIONS The clinical course of SSPE usually is divided into four phases (164,1851-1856). Phase I consists of irritability, for-getfulness, and generalized indifference. Affected children may develop behavior problems in school or be unable to perform their schoolwork adequately. Indeed, the initial manifestation of the disease in many children is failing grades. Some children, as well as adults, may be referred to a psychiatrist for an evaluation (1856). Others develop seizures (1857) and may be thought to have HSV encephali-tis until further progression occurs. Phase I lasts several weeks to about 3 months. Phase II is characterized by further intellectual deterioration, incoordination, and, most impor-tantly, involuntary movements. The classic abnormal move-ment is generalized axial myoclonus that often initially af-fects only one limb or group of muscles, but choreoathetoid movements may occur. Phase II may last several months or progress rapidly to phase III, which consists of a mute-like state with opisthotonus and decerebrate rigidity or decorti-cate posturing. This phase may last 2-4 months. Phase IV is characterized by continued dementia, hypotonic quadri-paresis, and a decrease in abnormal movements. The dura-tion of this phase is variable and may last years. Stupor, often with autonomic dysfunction, occurs during this stage and is followed by coma, with death being the inevitable result. The mean survival time without treatment is 18 months from the onset of symptoms, but some patients sur-vive for 3 years or longer (1858) and others die within a few months (1859,1860). Spontaneous long-term remissions have been reported (1861). Visual symptoms may be prominent in patients with SSPE, occurring at some time during the course of the dis-ease in about 50% of patients (1856). They may even be the presenting manifestation of the disease, preceding neuro-logic and psychiatric manifestations by as much as 2 years (1862,1863). Some patients develop disturbances of cerebral visual function that reflect the predilection of the virus for the parieto-occipital regions. These manifestations include cortical blindness, homonymous field defects, impaired spa-tial perception, visual agnosia, and both formed and un-formed visual hallucinations (1862-1868). Takayama et al. (1867), for example, described a 12-year-old girl with SSPE whose blurred vision was attributed to involvement of the lateral geniculate nuclei. Disturbances of fixation, ocular motility, and alignment, including nystagmus, supranuclear gaze pareses, ocular motor nerve pareses, and other involun-tary eye movements, can occur but usually do so late in the disease (1862,1869,1870). Disturbances in external appear-ance, including ptosis and proptosis, occur in rare patients (1862,1871). The most common intraocular manifestation is papilledema, which is present in about 16% of patients 3242 CLINICAL NEURO-OPHTHALMOLOGY (1856,1860,1872,1873) (Fig. 57.67). Such patients initially may be thought to have a space-occupying intracranial mass or pseudotumor cerebri. Other findings include optic neuri-tis, optic atrophy, retinal vasculitis, retinitis, and deep macu-lar or chorioretinal disturbances (1862,1874-1881). The predilection for a macular lesion to develop in patients with SSPE is extremely important because the lesion may be mistaken for ocular histoplasmosis, macular degeneration, central serous chorioretinopathy, or traumatic macular injury (1875,1882), particularly when it precedes any other mani-festations of the underlying disease. We saw such a case. The patient was a previously healthy 17-year-old girl who developed decreased vision in the left eye. She was found to have visual acuity of 20/15 OD and 20/200 OS. A pig-mentary lesion with some hemorrhage was noted in the left macula (Fig. 57.68), and a diagnosis of presumed ocular histoplasmosis was made. A fluorescein angiogram was per-formed and seemed to confirm the diagnosis, and the patient was therefore treated with argon laser photocoagulation. Over the next 3 months, the patient's visual acuity remained stable, but she began to perform poorly in school. She went from being a straight-A student to receiving C's and Ds, and she began to exhibit problems with behavior in class. She had been seeing a psychiatrist for about 3 weeks when she began to develop myoclonic jerks, and the diagnosis became clear. The chorioretinal lesions of SSPE typically affect the reti-nal pigment epithelium and deep layers of the retina, produc-ing a ground-glass whitening of the retina caused by edema Figure 57.67. Papilledema in subacute sclerosing panencephalitis (SSPE). Appearance of the right optic disc of a 7-year-old girl with a history of progressive somnolence and seizures. She had experienced an attack of typical measles in the first year of life. The right optic disc shows marked hyperemia and swelling, and several peripapillary hemorrhages are present. The left optic disc had a similar appearance. An evaluation that culminated in a brain biopsy confirmed a diagnosis of SSPE. (From Cherry PMH, Faulkner JD. A case of subacute sclerosing panencephalitis with exophthal-mos. Ann Ophthalmol 1975;7:1579-1586.) Figure 57.68. Maculopathy preceding the development of neurologic manifestations of subacute sclerosing panencephalitis (SSPE). The patient was a 17-year-old girl who reported decreased vision in the left eye. Visual acuity was 20/15 OD and 20/200 OS. The left ocular fundus shows macular edema associated with areas of intraretinal hemorrhage around and temporal to the fovea. The patient was thought to have the presumed ocular histoplas-mosis syndrome, and the macular lesions were treated with photocoagula-tion. Over the next 3 months, however, she developed behavior problems and difficulty with school work. She then developed myoclonic jerks. A diagnosis of SSPE was made by brain biopsy. associated over time with progressive pigment mottling (1862,1875,1877,1882-1886) (Figs. 57.69 and 57.70). Hemorrhage does not usually occur, but necrotizing retinitis does (1856,1876,1887).Asingle discrete lesion may be seen, or multiple lesions may be present. Acute multifocal placoid pigment epitheliopathy-like lesions may be an early present-ing feature (1881). In some patients, only the choriocapillaris is affected, and it is these patients in which central serous chorioretinopathy may be diagnosed. Multifocal subretinal lesions may occur (1878). The retinopathy may subside or become more severe as the disease progresses. In rare cases, there is spread to the vitreous, producing a mild preretinal haze or snowflake-like opacities (1888). A gliotic retinal scar associated with contracture of the inner limiting mem-brane may ultimately develop. The scar typically has a white center surrounded by hyperpigmentation. PATHOLOGY Brain biopsy performed in the early stages of SSPE shows mild inflammation of the meninges associated with a pa-nencephalitis affecting white matter and both cortical and subcortical gray matter (297,1171,1226,1810,1850,1855, 1859,1889-1892). Blood vessels in affected areas are cuffed by plasma cells and lymphocytes. Glial proliferation usually is present, and loss of myelin secondary to degeneration of neurons may be seen. Intranuclear and intracytoplasmic inclusions, called Cowdry inclusion bodies, are present in neurons, astrocytes, and oligodendrocytes. Electron micro- VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3243 Figure 57.69. Maculopathy preceding the development of neurologic manifestations of subacute sclerosing panencephalitis (SSPE). The patient was a 12-year-old boy with progressive visual loss in both eyes associated with lesions in both maculae. Visual acuity was 20/400 in the right eye and counting fingers at 4 feet in the left eye. A, The right macula shows several areas of whitening and edema. There is an unusual sheen to the posterior pole. B, The left posterior pole shows several areas of whitening and edema, particularly just nasal to the fovea. The patient gradually became lethargic, mute, and blind. As he did so, the macular lesions regressed and became replaced by pigmentary changes. C, Three weeks later, the right macula shows nonspecific pigmentary changes. D, The left macula shows a similar appearance. Note marked constriction of retinal arteries and pallor of the optic disc. The patient died 3 months after the onset of his disease, at which time a postmortem examination established a diagnosis of SSPE. (From Landers MB III, Klintworth GK. Subacute sclerosing panencephalitis [SSPE]: a clinicopathologic study of the retinal lesions. Arch Ophthalmol 1971;86 156-163.) scopic examination of these bodies reveals that they contain measles virus nucleocapsids; however, the nucleocapsids are not enclosed by a lipid envelope, and no complete measles virions are seen (1889,1890). Measles virus antigens can be demonstrated by labeled-antibody techniques within the inclusions as well as in cells that contain no inclusions. The main pathologic findings observed in the brains of patients with SSPE at autopsy are necrosis and gliosis (1171,1888). Neurofibrillary tangle formation may occur (1891), but almost no evidence of inflammation is present by the time of the patient's death (1855). The ocular pathology in patients with SSPE consists of retinal atrophy and gliosis of the retina and optic nerve (233) (Fig. 57.71). Intranuclear inclusions are observed in reti-nal neurons (1876,1893,1894). Immunofluorescence studies demonstrate measles virus antigen in the infected retinal cells, and immuno-ultrastructural methods, using horserad-ish peroxidase-conjugated antibodies, show both intranu-clear and intracytoplasmic viral nucleocapsids in the retina (1895). Even patients without overt ophthalmoscopic evi-dence of retinal lesions may show these pathologic changes (1893). 3244 CLINICAL NEURO-OPHTHALMOLOGY Figure 57.70. Maculopathy associated with subacute sclerosing panencephalitis. A, Appearance of the left macula of an 11- year-old boy with SSPE. There is marked perimacular depigmentation associated with a hyperpigmented scar. No underlying choroidal vessels are seen. B, Appearance of the right macula of a 12-year-old boy. There is a large macular scar, the center of which is hypopigmented. Hyperpigmented ‘splinters'' partially surround the lesion. Note subtle contraction of the inner limiting membrane. (From Green SH, Wirtschafter JD. Ophthalmoscopic findings in subacute sclerosing panencephalitis. Br JOphthalmol 1973;57 780-787.) PATHOGENESIS SSPE is related to persistent infection with measles virus; however, the genomes of strains of measles virus that are isolated from patients with SSPE seem to be different from those isolated from typical cases of measles (1896,1897). These genomes tend to be larger and contain multiple muta-tions. The defective virus is present in large quantities in brains of SSPE patients, as demonstrated by electron micro-scopic examination and by immunofluorescent antibody techniques (1898). High titers of both IgG and IgM antibod-ies to measles virus are found in the serum and CSF during the disease, and the titers may continue to rise as the disease progresses (1899,1900). CSF flow studies, using radioiso-tope- labeled IgG (1901), and studies of oligoclonal IgG anti-bodies in CSF (1902) provide direct evidence that these anti-bodies are synthesized within the CNS. Thus, the virus apparently replicates, and the disease progresses, despite high levels of humoral antibody. It is therefore postulated that measles virus infection early in life, when passive mater-nal immunity is present and the host immune response is immature, allows establishment of chronic infection and se-lection of cell-associated neurotropic mutants of measles virus that eventually produce SSPE (1898); on the other hand, the host immune response may be more important in the cause of SSPE than the virus itself (1903). The high levels of measles antibody are not protective and might be harmful. Nagano et al. (1904) found more CD4 lympho-cytes than CD8 lymphocytes both in the brain parenchyma and perivascular cuffs of patients with SSPE. These findings suggest that CD4 cells may be involved in the pathogene-sis of the disease. Nagano et al. (1904) also found a variety of cytokines in brain lesions from patients with SSPE, again suggesting that an immune reaction may play a role in the development or severity of the disease. Perhaps both mecha-nisms- chronic infection by a mutant measles virus and a hyperimmune host response-are together responsible for SSPE (1810); however, the pathogenesis of this disease re-mains to be elucidated. DIAGNOSIS The diagnosis of SSPE may be suspected on clinical grounds, particularly when a child or young adult develops progressive mental deterioration associated with myoclonus. A history of measles at an early age provides further support for the diagnosis. There is often a typical EEG disturbance consisting of bilateral periodic bursts of high-voltage activity every 3-20 seconds, with background suppression (1892, 1893,1905). Neuroimaging studies show progressive cere-bral atrophy and diffuse disturbances of the white and gray matter of the brain, often starting in the occipital lobes (1906-1909,1909a). In the early stages, MRimaging reveals lesions usually involving the parieto-occipital cortico-sub-cortical regions asymmetrically. In time, symmetric periven-tricular white matter changes become more prominent (1909,1909b). The results of MR spectroscopy suggest that inflammation and glial proliferation occur before neuronal loss in MR-negative regions as well as MR-positive regions (1909a,1910,1911,1911a). Analysis of CSF typically reveals VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3245 Figure 57.71. Ocular pathology in subacute sclerosing panencephalitis. The patient was a 13-year-old girl who died 2 months after the onset of the disease. Visual loss occurred shortly before the onset of neurologic manifestations of the disease. A, Right ocular fundus shows a slightly elevated, yellowish lesion in the macula and two smaller lesions just temporal to the macula (arrowheads). B, Left ocular fundus shows abnormal pigmentation in the macula associated with an abnormal radiating pattern of the light reflex from the inner surface of the retina (arrowheads). The patient subsequently died of the effects of the disease. C, Section through the macula of the left eye shows loss of lamellar architecture with intraretinal gliosis (arrows) and apparent contraction and wrinkling of the inner limiting membrane (arrowhead). (From Nelson DA, Weiner A, Yanoff M, et al. Retinal lesions in subacute sclerosing panencephalitis. Arch Ophthalmol 1970;84 613-621.) increased protein caused by elevated oligoclonal IgG anti-bodies against measles antigens (1808,1846,1912), and PCR with nucleic acid probes can be used to identify RNA spe-cific for measles virus in the brain (1819,1846,1913). TREATMENT AND PROGNOSIS Untreated SSPE almost always ends in death within 6 months to 7 years after the onset of symptoms (1914), al-though rare patients experience a spontaneous remission (1861). Unfortunately, there is no uniformly successful treat-ment for SSPE. Several drugs have been tried, including intrathecal, intraventricular, or subcutaneous interferon-alpha, oral isoprinosine, intravenous or intraventricular ri-bavirin, and oral lamivudine, with these agents usually given in various combinations (1915-1926). The therapies can be monitored by measuring measles virus RNA by quantitative PCR assays (1925). Although all of these drugs, alone or in combination, may slow the progression of the disease, death remains the ultimate outcome in most patients (1927). Paramyxoviruses The genus Paramyxovirus contains several different spe-cies of virus, including the mumps virus, Nipah virus, parain-fluenza viruses, and Newcastle disease virus. Of these, only the mumps virus and Nipah virus cause significant neuro-logic disease, although parainfluenza viruses occasionally cause aseptic meningitis in persons of all ages. Mumps Virus The mumps virus is the most important of the paramyxovi-ruses from a neuro-ophthalmologic standpoint. It causes a disease called mumps, which has significant neurologic, vis-ual, and neuro-ophthalmologic manifestations. CHARACTERISTICS The mumps virus is an enveloped RNA virus that has an external surface covered by glycoproteins possessing hem- 3246 CLINICAL NEURO-OPHTHALMOLOGY agglutinin activity, neuraminidase activity, and cell fusion activity (1928). A viral antigen (V) is associated with this layer. The middle layer of the envelope is actually a lipid bilayer that is acquired from the host cell as the virus buds off the cytoplasmic membrane. The inner surface of the en-velope is a nonglycosylated membrane protein that main-tains the outer structure of the virus. The genome of the virus is contained in a nucleocapsid that has a helical structure composed of a continuous linear molecule of single-stranded RNA surrounded by symmetrically repeating protein sub-units. The capsid protein carries RNA polymerase activity, and the nucleocapsid is responsible for the soluble (S) anti-gen that is detectable early in mumps virus infection. Only one serotype of mumps virus is known. EPIDEMIOLOGY Humans are the only known natural host for the mumps virus, although nonhuman primates and other laboratory ani-mals can be experimentally infected. Infection with mumps virus produces mumps. The etymology of the term is unclear. It may have arisen from the English noun mump, meaning ‘‘lump,'' or the English adjective mump, meaning ‘‘sulky,'' a description of the characteristic facial expression of af-fected persons. Alternatively, the term may have originated from the typical mumbling speech pattern of people with the disease (1928). Mumps is endemic throughout the world. Before a vaccine was available and active programs requiring vaccination were developed, epidemics occurred every 2-5 years. Al-though there has been a 98% decline in the incidence of mumps in the United States since 1967, the disease still occurs throughout the year, with a peak incidence between January and May and an incidence of about 1 per 100,000 persons per year (1928). The number of cases continues to decline (1929), presumably because aggressive immuniza-tion programs prevent the disease. Epidemics of mumps oc-casionally occur in military populations and other closed communities, including prisons, boarding schools, ships, and remote islands (1930). The disease usually is spread through the community by unvaccinated children who become in-fected in school and who subsequently infect susceptible family members. Mumps is uncommon in infants less than 1 year of age because of passive immunity acquired by the placental trans-fer of maternal antibody to the mumps virus (1928). In the prevaccine era, over 50% of cases occurred in children be-tween 5 and 9 years old, and 90% of cases occurred in chil-dren younger than 14 years of age. Since mumps vaccine was made available in the United States, only 25% of cases occur in children under 10 years old. More than 50% of cases occur in the second decade of life. PATHOGENESIS The mumps virus is transmitted via direct contact, drop-lets, or fomites. It enters the body through the nose or mouth. Experimental studies suggest that the virus proliferates in the epithelial cells of the upper respiratory tract, following which a viremia develops, during which the virus is dissemi-nated to glandular and neural tissue (1928). The virus is transmitted to the CNS either as free particles in plasma or, more likely, by infected host mononuclear cells (1931,1932). The virus is thought to spread across the endothelium of the choroid plexus and to infect choroidal epithelial cells. Replication of the virus then occurs in the choroidal epithe-lium, and progeny virus is shed into the CSF. CLINICAL MANIFESTATIONS After an incubation period of 16-18 days (range, 2-4 weeks), prodromal symptoms begin, including low-grade fever, anorexia, malaise, and headache (1933). Within a day, the nature of the illness becomes apparent when the patient reports an earache and tenderness to palpation of the ipsi-lateral parotid gland (1928). The affected gland becomes visibly enlarged within 24 hours, with progression to maxi-mum size occurring over 2-3 days associated with severe pain. The orifice of Stensen's duct is often edematous, and the enlargement of the parotid gland often lifts the ear lobe outward, obscuring the angle of the mandible. Seventy-five percent of patients eventually develop bilateral parotitis, with one gland usually enlarging a few days before the other. About 25% of patients with mumps develop pure unilateral parotitis. The parotitis of mumps produces a number of symptoms. Trismus may occur, and the patient may have difficulty with both pronunciation and mastication. Ingestion of citrus fruits or juices typically exacerbates the pain. Patients with mumps often become febrile during the first 3 days of the illness. Once parotid swelling peaks, the fever, tenderness, and pain rapidly resolve, and the gland returns to normal size within about 1 week. Salivary glands other than the parotid are affected during an attack of mumps in about 10% of patients; however, extra-parotid salivary involvement is almost never the sole mani-festation of the disease. The submandibular glands are the most common salivary glands affected after the parotids, with the sublingual glands being the least frequently af-fected. COMPLICATIONS Patients with mumps may develop a number of systemic, ocular, neurologic, and neuro-ophthalmologic complica-tions. The major systemic complications include (a) epidi-dymitis with orchitis (the most common extrasalivary gland manifestation of mumps in adult men), which may result in some degree of testicular atrophy; (b) oophoritis, occurring in about 5% of postpubertal women with mumps; (c) arthri-tis, which may occur in both adults and children; (d) pancre-atitis; (e) cardiac disturbances, including asymptomatic changes in the electrocardiogram and fatal myocarditis; (f) renal dysfunction; and (g) spontaneous abortion in women who develop mumps during pregnancy (1928). Although a variety of congenital malformations occur in infants born to women whose pregnancy is complicated by mumps, it would seem from several studies that the incidence and nature of such malformations are no greater than in control newborn populations (1934,1935). VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3247 The ocular complications of mumps are numerous and varied. Many occur in the absence of any evidence of neuro-logic dysfunction. Conjunctivitis is a particularly common complication (1936). It is follicular and invariably bilateral. Dacryoadenitis is also a common complication of mumps (1936). It tends to be bilateral unless there is unilateral par-otid involvement, in which case it usually occurs on the side of the affected parotid gland. Iritis and iridocyclitis occur in rare patients with mumps (1936). The inflammation usually is mild, but it may be so severe that peripheral anterior sy-nechiae develop, causing secondary glaucoma and perma-nent loss of vision. Other patients develop secondary cata-racts from persistent uveitis associated with otherwise uncomplicated mumps. Keratitis may develop in patients with mumps. It usually develops 2-11 days after the onset of the disease, is unilateral, and is associated with iritis (1937,1938). Retinal vascular complications occasionally occur in pa-tients with mumps. Riffenburgh (1939) reported that central retinal vein occlusion occasionally occurred and suggested that the enlarged parotid gland might somehow slow venous flow from the orbit and contribute to the condition. We doubt the validity of this hypothesis, given the normal venous drainage of the eye. Although epididymitis with orchitis is the most common extrasalivary gland manifestation of mumps in adult men, the most common extrasalivary gland complication overall, occurring in about 60% of patients with mumps, is involve-ment of the CNS (1933). Males and females have the same incidence of mumps parotitis, but there is a distinct male predominance with respect to the development of mumps-associated CNS disease among children (1933). The ratio of affected males to females is 3 1 to 4 1 in almost every published series (1714,1940,1941). We have no explanation for the striking difference in the incidence of CNS disease associated with mumps between the two sexes in children, and it is even more bothersome when one considers that among young adults with CNS disease caused by mumps, the ratio of affected males to females is closer to 1 1 (1942). The peak age of CNS involvement in mumps is about 7 years in both sexes (1942), with 60-70% of all cases occurring in children between 5 and 9 years old (972,1943,1944). CNS manifestations of mumps include asymptomatic CSF pleocytosis, meningitis, encephalitis, and a number of less common disorders. In nonimmunized populations, mumps is one of the most common causes of both aseptic meningitis and encephalitis (164,1170,1171,1714,1945,1946). In fact, CNS involvement in mumps is so common that some authors consider it a part of the natural history of the disease, not a complication (1933). Some authors also consider the menin-gitis and the encephalitis caused by mumps as a single entity, ‘‘mumps meningoencephalitis.'' Although the two disorders do overlap considerably in some patients, the use of this term obscures the fact that persons who develop aseptic men-ingitis caused by mumps have a much more benign course and prognosis than do persons who develop mumps encepha-litis. We thus consider these disorders as separate entities in this chapter. The most common CNS manifestation of mumps, occur-ring in over 50% of patients, is asymptomatic CSF pleo-cytosis (1947,1948). Patients with this process have no clini-cal evidence of meningeal irritation, nor do they manifest any changes in consciousness, behavior, or neurologic func-tion. Clinical evidence of meningitis develops in 1-10% of patients with mumps (1943,1944,1949,1950). Symptoms and signs of mumps meningitis are nonspecific and typical of viral meningitis. They include headache, fever, nuchal rigidity, and vomiting. Papilledema is rare (1951). These manifestations usually develop about 4 days after the onset of salivary gland involvement; however, they may occur as early as 1 week before, simultaneous with, or 2 weeks after such involvement (1943,1944,1948-1950). In addition, 40-50% of patients with proven mumps meningitis have no evidence of enlargement of the salivary glands (1944,1952). Lumbar puncture in patients with mumps meningitis usu-ally reveals a number of abnormalities (1943,1944). The CSF may be under increased pressure, and there usually is a pleocytosis that ranges from 10 to 2,000 white blood cells/ mm3. In most patients, the pleocytosis is lymphocytic; how-ever, about 20-25% of patients have a predominance of PMNs. Protein concentration in the CSF may be normal or moderately increased, with 90-95% of patients having a CSF protein concentration of less than 70 mg/dL. The con-centration of glucose in the CSF usually is normal in patients with mumps. Nevertheless, 6-30% of patients have hypo-glycorrhachia, an unusual finding in most other viral menin-gitides. All of these abnormalities are present for 5 weeks or longer, but the symptoms subside within 3-10 days, and there usually is complete recovery with no sequelae. Some patients, however, develop obstructive hydrocephalus from aqueductal stenosis or obstruction of the foramen of Munro, caused by ependymitis (1953,1954). Encephalitis develops in 1 in 400 to 1 in 6,000 cases of mumps (1955-1957). There seems to be a bimodal distribu-tion with respect to the time of onset of this complication. Encephalitis may develop coincident with the onset of par-otitis or before, in which case it is caused by viral invasion of the CNS, as is HSV encephalitis (1958). Alternatively, encephalitis may develop 7-10 days after the onset of paroti-tis, in which case it is thought to be an immune-mediated, postinfectious demyelinating process (i.e., ADEM) caused by the response of the host to the infection (1928,1959). The clinical features of mumps encephalitis are generally nonfocal. They include a marked reduction in the level of consciousness, convulsions, paresis, aphasia, and involun-tary movements of the arms and legs. The condition initially may mimic HSV encephalitis, particularly when it occurs before or in the absence of other manifestations of mumps (1960). Some patients develop a brain stem or cerebellar encephalitis (1956,1957). Others develop cranial neuropa-thies, including unilateral or bilateral facial nerve pareses and unilateral or bilateral ocular motor nerve pareses, most often affecting the abducens or oculomotor nerves (1961). The vestibulocochlear nerve may be affected, producing uni-lateral or occasionally bilateral deafness (1962), nystagmus, or both. Conjugate gaze pareses also may occur in patients with evidence of brain stem dysfunction in this setting 3248 CLINICAL NEURO-OPHTHALMOLOGY (1963), as may opsoclonus associated with body tremor (1964). Patients with mumps encephalitis typically have a high fever. Analysis of CSF in these patients shows findings iden-tical with those seen in patients with mumps meningitis, including a pleocytosis that usually is lymphocytic, an in-creased protein concentration, and a normal or low concen-tration of glucose. The prognosis in cases of mumps encephalitis is generally excellent (1789). Patients usually experience gradual resolu-tion of neurologic signs and symptoms over 1-2 weeks. Many patients have no sequelae, but some have persistent seizures, psychomotor retardation, or both (345,1943,1944, 1949), and others have permanent complete or partial deaf-ness (1962). A patient described by Simon (1963) had a persistent paralysis of downward gaze associated with defec-tive caloric and optokinetic responses. Death occurs in less than 2% of cases. Neurologic manifestations other than meningitis and en-cephalitis develop in rare patients with mumps (1965). Iso-lated facial nerve paresis, isolated deafness that may be tran-sient or permanent, cerebellar ataxia, transverse myelitis, Guillain-Barre´ syndrome, and a poliomyelitis-like syndrome can all occur (377,1966). Tho¨mke and Hopf (1967) de-scribed a 36-year-old man in whom unilateral vestibular pa-ralysis was the sole manifestation of mumps. The patient experienced the sudden onset of rotational vertigo associated with nausea, vomiting, and postural imbalance. Examination revealed a spontaneous horizontal-torsional nystagmus with the fast phase counterclockwise. The nystagmus increased on rightward gaze. An electro-oculogram confirmed a left vestibular paralysis. There was a mild peripheral leukocyto-sis, and the CSF showed a mild lymphocytic pleocytosis with a normal concentration of both protein and glucose. Serum antibody testing, using ELISA, revealed increased titers of antibody to mumps virus. The titers increased over the next 2 months, during which time the patient experienced marked improvement in his symptoms. He was never febrile, nor did he ever develop a rash. A wide variety of complications of neuro-ophthalmologic significance may develop in patients with mumps. Pupillary dilation and anisocoria are not infrequent in patients with mumps meningitis (1968). Paralysis of accommodation may also occur, although it usually is transient (1969,1970). Pa-ralysis of the oculomotor nerve occurs infrequently and may or may not be associated with pupillary involvement. Optic neuritis is an infrequent complication of mumps (1939). It can occur as early as 5 days after the onset of the rash or more than 1 month afterward (1936). The optic neuri-tis usually is of the anterior type (i.e., there is optic disc swelling) and bilateral; however, Woodward (1936) de-scribed an 11-year-old child who developed a purely unilat-eral anterior optic neuritis. The degree of visual loss in mumps-associated optic neuritis may be extremely severe (1971-1973) or fairly mild (1936). A macular star figure composed of lipid develops in some of patients, producing the picture of a neuroretinitis (1939,1974,1975) (Fig. 57.72). Recovery is the rule, but permanent visual loss may occur, and most patients have residual optic atrophy, regardless of the initial appearance of the optic discs or the final level of vision. Patients with mumps occasionally develop asymptomatic optic neuritis that can be detected with MR imaging. Sugita et al. (1959) described a 5-year-old boy who developed an acute disseminated encephalomyelitis shortly after experi-encing a typical attack of mumps. MR imaging was per-formed as part of the evaluation and revealed a clinically silent abnormality consistent with demyelination in the right optic nerve, even though there was no clinical evidence of an optic neuritis. Visual evoked responses confirmed delayed conduction in the right optic nerve compared with the left. As noted earlier, papilledema occasionally develops in patients with mumps meningitis (1951). It usually resolves without producing visual sequelae. Gibberd and Kelly (1976) described three patients who developed a polyradiculitis mainly affecting motor neurons. All three patients had both internal and external ophthalmo-paresis. All three showed increased antibody titers to mumps virus. Davis et al. (1977) described a patient with mumps who developed cerebellar ataxia. During the illness, the patient also experienced transient cortical blindness from which he completely recovered. DIAGNOSIS The diagnosis of mumps usually is easily made on clinical grounds, particularly when there is parotid swelling and ten-derness associated with constitutional symptoms. A history of exposure to a patient with mumps corroborates the diagno-sis, and laboratory confirmation in such cases usually is un-necessary. When parotitis is absent, however, or when pa-tients develop prominent extrasalivary gland manifestations, a variety of diagnostic tests may be used to confirm the diagnosis. The virus may be isolated from a number of sources. It usually is present in saliva for about 1 week, usually 2-3 days before and 4-5 days after the onset of parotitis. It can be isolated from the blood but only within a few days of the onset of symptoms; however, a viruria may be present for several weeks. The virus also can be isolated from CSF in patients with clinical meningitis and early-onset encephali-tis. The use of PCR and nucleic acid probes for mumps virus RNA may greatly increase the speed and accuracy of the diagnosis (1978). Serologic studies, using acute and convalescent sera to detect antibody to mumps virus antigen, are fairly sensitive and specific for the diagnosis of mumps, but they do not yield a definitive diagnosis for several weeks. An ELISA study of CSF may establish the diagnosis in cases of mumps meningitis (1979). TREATMENT AND PROGNOSIS There is no specific therapy for mumps. Supportive treat-ment includes antipyretics to reduce fever and analgesics to relieve the pain of parotitis and, when present, epididymitis VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3249 Figure 57.72. Neuroretinitis associated with mumps. The patient was a 15-year-old boy who experienced a typi-cal attack of mumps that was characterized by fever, retro-orbital headache, and swelling of the left face and neck. He then noted progressive loss of vision in the right eye. Visual acuity was 20/200 in the right eye and 20/20 in the left eye. The visual field of the right eye showed a cecocentral scotoma, and there was a right relative afferent pupillary defect. There was no reaction in the anterior chamber of the right eye, but there were cells in the poste-rior vitreous. A, CT scan shows an enlarged left parotid gland (arrow). The scan showed no intracranial abnormali-ties. B, The right ocular fundus shows a swollen hyperemic optic disc associated with a star figure composed of hard exudate in the macula. Lumbar puncture revealed a lymphocytic pleocytosis, hypoglycorrhachia, and an in-creased concentration of protein. The patient was treated with systemic corticosteroids and subsequently experi-enced improvement in visual function. C, Neuroretinitis affecting the right eye of an 8-year-old boy whose sister had experienced an attack of mumps 2 weeks earlier. The patient himself did not have evidence of mumps, but it was postulated that the neuroretinitis was caused by subclinical infection with mumps virus. (A and B, From Foster RE, Lowder CY, Meisler DM, et al. Mumps neuroretinitis in an adolescent. Am JOphthalmol 1990;110 91-93. C, From Glaser JS. Neuro-Ophthalmology. Hagerstown, MD: Harper & Row, 1978 85.) and orchitis. Topical application of warm or cold compresses to the affected areas may also reduce discomfort. Most patients experience complete resolution of symp-toms and signs within 1-2 weeks. Once an attack has oc-curred, there will be no further attacks because a single attack confers lifelong immunity. As noted earlier, mumps menin-gitis also is a benign, self-limited condition, whereas mumps encephalitis has a definite, although low, mortality and mor-bidity. PREVENTION Active immunization with a live attenuated mumps virus vaccine has been used in the United States since 1967 (1928). A single subcutaneous inoculation produces protective lev-els of mumps-neutralizing antibody in more than 95% of vaccinees (1928), and satisfactory titers are maintained for at least 10 years. There are occasional vaccination failures. For example, some adolescents and adults lack protective mumps antibody titers after seemingly appropriate vaccina-tion. Adverse reactions to the mumps vaccine are said to be rare, but isolated unilateral or bilateral hearing loss occasion-ally occurs (1980). An aseptic meningitis associated with mumps virus in the CSF develops in up to 0.7% of children 11-28 days after vaccination (1823,1981-1986), and rare patients develop a meningoencephalitis after receiving the mumps vaccine (1987). Mumps virus vaccine usually is given as a combined MMR vaccine to all children over 12 months of age, usually around age 15 months. Because of the risk of epididymitis and orchitis in postpubertal men who develop mumps, im-munization may also be considered for male adolescents and adults without a history of mumps. As with most other live virus vaccines, mumps vaccine should not be given to preg- 3250 CLINICAL NEURO-OPHTHALMOLOGY nant women or patients who are immunosuppressed by drugs or disease. Nipah Virus A previously unknown paramyxovirus was identified as the etiologic agent of an outbreak of severe encephalitis in people with close contact exposure to pigs in Malaysia and Singapore between September 1998 and June 1999 (322,1988-1999). This virus was subsequently named Nipah virus after the Malaysian village of a patient from whose brain the virus was first isolated (1988,1991). Almost all affected cases were male subjects involved in pig farming or related industries. Pigs were the reservoir of infection, with infection transmitted by respiratory aerosols to humans who were dead-end hosts. The pathogenesis of the Nipah infection is associated with its ability to infect blood vessels and extravascular paren-chyma in many organs, particularly the CNS (1989). Nipah virus encephalitis thus is predominantly a CNS vasculitis with endothelial cell infection, resulting in vascular throm-bosis and subsequent tissue infarction. In a study of the clinical features of 103 patients with Nipah encephalitis (1990), the mean age of affected individ-uals was 38 years. Eighty-nine percent of the cases were male, 58% were ethnic Chinese, and 78% were owners of pig farms or workers on those farms. The mean incubation period was 10 days. The patients typically presented with nonspecific systemic symptoms of fever, headache, myal-gias, and sore throat. Seizures and focal neurologic signs were seen in 16% and 5%, respectively. In more severe cases, these findings were followed by drowsiness and dete-riorating consciousness requiring ventilation in 61% of pa-tients. Autonomic disturbances and myoclonic jerks were common features. The mortality was 41%. Systolic hyper-tension, tachycardia, and high fever were associated with a poor outcome. Forty percent recovered fully; the other 19% had mostly mild neurologic residua (1990). Goh et al. (1991) reported 94 patients with Nipah virus encephalitis. The mean age was 37 years with a male-to-female ratio of 4.5 1. Ninety-three percent had direct contact with pigs, usually in the 2 weeks before onset of illness. The main presenting features were fever, headache, dizziness, and vomiting. Fifty-five percent of patients had a reduced level of consciousness and prominent brain stem dysfunc-tion. Distinctive clinical signs included segmental myoclo-nus, areflexia and hypotonia, hypertension, and tachycardia, suggesting brain stem and upper cervical spinal cord in-volvement. Antibodies against Nipah virus were detected in the serum and CSF in 76% of patients. Thirty-two percent of the patients died. Neurologic relapse occurred after ini-tially mild disease in three patients. Fifty-three percent of patients fully recovered, whereas 15% had persistent neuro-logic deficits. MR imaging in cases of Nipah encephalitis reveals dis-crete small lesions or patchy areas of confluent abnormali-ties, mainly in the subcortical and deep white matter of the cerebral hemispheres (1993,1994,1996-1998). Diffusion-weighted MR images show a decrease in the prominence or disappearance of lesions over time (1998). Other reports of the neurologic manifestations of Nipah infection describe patients with aseptic meningitis, focal brain stem signs, and cerebellar signs (1998). Tan et al. (1994) reported that some survivors of acute Nipah encepha-litis experienced episodes of recurrent encephalitis, and some patients with acute infection not involving the CNS or asymptomatic infection developed encephalitis at a later date (late-onset encephalitis), with the mean interval be-tween the initial infection and the first neurologic episode being 8.4 months. Lim et al. (1993) reported follow-up of patients with Nipah encephalitis and mentioned the occurrence of retinal artery occlusion in one patient, Horner syndrome from cervi-cal cord involvement in one patient, and residual abducens nerve palsy in one patient. High mortality with Nipah en-cephalitis correlates with the presence of virus in the CSF, suggesting that high viral replication in the CNS may be an important factor for high mortality (1995). The main histopathologic findings with Nipah encephali-tis include a systemic vasculitis with extensive thrombosis and parenchymal necrosis, particularly in the CNS (1999). Endothelial damage, necrosis, and syncytial giant cell forma-tion are seen in the affected vessels. Characteristic viral in-clusions are seen by light and electron microscopy (1999). Immunohistochemical analysis shows widespread Nipah virus antigen in endothelial and smooth muscle cells of blood vessels. Abundant viral antigens are also seen in various parenchymal cells, particularly in neurons. Thus, infection of endothelial cells and neurons, vasculitis, and thrombosis seem to be critical to the pathogenesis of this disease (1999). An open-label trial of ribavirin for Nipah virus encephali-tis revealed that this drug reduced mortality from 54% to 32% and may have improved outcome in survivors (2000). Parainfluenza Viruses The parainfluenza viruses are primarily pathogens of the respiratory tract and are important causes of both upper and lower respiratory tract infections. There are four serotypes of human parainfluenza viruses, types 1-4 (2001). The most common manifestations of infection with para-influenza viruses are respiratory. As noted earlier, however, these viruses occasionally infect the CNS. Like other respiratory tract pathogens, parainfluenza vi-ruses cause a variety of clinical syndromes that range from mild upper respiratory tract illness to severe lower respira-tory tract infection. These viruses are the leading cause of viral laryngotracheobronchitis (croup), accounting for more than 40% of cases (2002). The viruses may also cause pneu-monia, bronchiolitis, and bronchitis (2003,2004). The type of respiratory tract disease caused by parainflu-enza viruses depends not only on their serotype but also on the age of the patient. With increasing age, primary infection with one of the viral serotypes is less likely to cause severe lower respiratory tract disease, and reinfection, although not uncommon throughout life, also is unlikely to produce lower respiratory tract disease. Thus, adults who experience a pri- VIRUSES (EXCEPT RETROVIRUSES) AND VIRAL DISEASES 3251 mary infection or reinfection with any of the parainfluenza virus serotypes almost always experience an upper respira-tory tract infection. Parainfluenza viruses can cause pro-longed and severe respiratory infection in children with im-munodeficiency from drugs or disease. In such cases, dissemination of the virus may occur (1707,2005). Cases of infection of the CNS by parainfluenza virus usu-ally are caused by serotype 3. It is thought that the parainflu-enza virus directly accesses the CNS via olfactory neurons and establishes long-term persistence in the nerve tissue. Although parainfluenza virus type 3 may cause fetal enceph-alitis and hydrocephalus via intrauterine infection (2006), most cases of CNS involvement occur in infants or young children and are characterized by an aseptic meningitis (2005,2007-2010). Meningitis apparently caused by parain-fluenza virus infection can also occur in adults (2008). Fe-brile seizures (2011), meningoencephalitis (2012), and ADEM (2013) also can occur in association with parainflu-enza virus infection. Roman et al. (2014) described a 19- year-old man who developed typical Guillain-Barre´ syn-drome in association with parainfluenza virus infection, and Vreede et al. (2009) isolated parainfluenza virus type 3 from the CSF of a 37-year-old woman who developed a demyelin-ating syndrome. Thus, parainfluenza viruses have the poten-tial to cause neurologic dysfunction not only by directly in-vading the CNS but also perhaps through an immune-mediated reaction. Pneumoviruses (Respiratory Syncytial Virus) Respiratory syncytial virus (RSV) belongs to the genus Pneumovirus (2015). RSV is the major cause of lower respi-ratory tract illness in young children, producing pneumonia, bronchiolitis, and tracheobronchitis (2015). Outbreaks usu-ally begin in late fall or early winter and persist until spring (2016). Children 2-6 months of age are at greatest risk for serious manifestations; however, children of any age with underlying cardiac or pulmonary disease or those who are immunocompromised are at risk for serious complications of this infection. In adults, RSV usually causes upper respira-tory tract infections, but it can cause serious lower respira-tory tract disease, particularly in the elderly and in persons with compromised immune systems (2